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Abstract:

Disclosed are pharmaceutical compositions and methods for the
administration of
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol or a pharmaceutically acceptable salt thereof and related compounds
for the treatment of neurological disorder such as Parkinson's disease
and restless leg syndrome.

Claims:

1. A pharmaceutical composition for delivery across the oral mucosa,
nasal mucosa or skin comprising
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

2. (canceled)

3. The pharmaceutical composition of claim 1 for delivery across the oral
mucosa comprising
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

4. (canceled)

5. The pharmaceutical composition of claim 3 wherein the delivery across
the oral mucosa occurs through oral buccal route, sublingual route or
through the lips.

Description:

FIELD OF THE INVENTION

[0001] The present invention relates to methods of administering
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol for the treatment of neurological disorders and pharmaceutical
compositions thereof.

BACKGROUND ART

[0002] The use of dopamine-replacing agents in the symptomatic treatment
of Parkinson's disease (PD) has undoubtedly been successful in increasing
the quality of life of patients. L-DOPA, which has been used for many
years and remains the gold standard for treatment of PD, alleviates motor
symptoms of PD characterized by the slowness of movement (bradykinesia),
rigidity and/or tremor. It is understood that L-DOPA acts as a prodrug
which is bio-metabolized into dopamine (DA). DA in turn activates
dopamine receptors in the brain which fall into two classes: D1 and D2
receptors. D1 receptors can be divided into D1 and D5 receptors
while D2 receptors can be divided into D2, D3, and D4
receptors. However, dopamine-replacement therapy does have limitations,
especially following long-term treatment.

[0003] PD afflicted patients may cycle between "on" periods in which
normal functioning is attained and "off" periods in which they are
severely parkinsonian. Additionally, as a consequence they may experience
profound disability despite the fact that L-DOPA remains an effective
anti-Parkinson agent throughout the course of the disease (Obeso, J A, et
al. Neurology 2000, 55, S13-23). It is worth noting that DA agonists do
cause less dyskinesia than L-DOPA but this is of limited value to PD
patients with dyskinesias because many of them have moderate-to-severe PD
and often they need the efficacy of L-DOPA.

[0004] Anti-Parkinson agents that mimic the action of DA have been shown
to be effective in treating PD. Selective D2-agonists such as Pramipexole
are effective but lack efficacy in late PD and eventually need
complementation or replacement with L-DOPA. Apomorphine is a
catecholamine anti-Parkinson's agent that acts as a potent D1/D2 agonist.
In particular, this drug is useful as a rescue during the "off" periods
of severely disabled patients who have received chronic L-DOPA treatment.
However, due to its poor oral bioavailability and high first-pass effect,
apomorphine is limited in its clinical application. To overcome the high
first pass effect and poor oral bioavailability, apomorphine must be
administered subcutaneously. Generally, the poor oral bio availability of
catecholamines has prevented their clinical use as orally administered
drugs.

[0005] Apart from PD, other diseases in which an increase in dopaminergic
turnover may be beneficial include treating depression and for the
improvement of mental functions including various aspects of cognition.
Dopaminergic turnover can have a positive effect on the treatment of
obesity as an anorectic agent. It can improve minimal brain dysfunction
(MBD), narcolepsy, and potentially the negative, the positive as well as
the cognitive symptoms of schizophrenia. Restless leg syndrome (RLS) and
periodic limb movement disorder (PLMD) are alternative indications, which
are clinically treated with DA agonists.

[0006] In addition, impotence and erectile dysfunction are also likely to
be improved by treatment with DA agonists. Thus, improvement of sexual
functions in both women and men is another possible indication for
treatment with DA agonists since erectile dysfunction (impotence in men)
and sexual stimulation in e.g. menopausal women (stimulation of vaginal
lubrication and erection of clitoris) potentially can be achieved via DA
receptor stimulation. In this context, it is noteworthy that apomorphine
when given sublingually is used clinically to improve erectile
dysfunction.

[0007] Clinical studies of L-DOPA and the D2 agonist Pramipexole as
therapies in Huntington's disease have shown promising results; thus
treatment of Huntington's disease is another potential application of the
compounds of the invention. DA is involved in regulation of the
cardiovascular and renal systems, and accordingly, renal failure and
hypertension can be considered alternative indications for the compounds
of the invention.

[0008] Despite the long-standing interest in the field, there is evidently
an unmet need for developing efficient and active drugs for the treatment
of PD. A mixed D1/D2 agonist giving continuous dopaminergic stimulation
may fulfil such unmet needs. To this end,
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol [herein referred to as Compound 10] has been identified as a potent
D1/D2 agonist which shows potential to treat PD. However, as previously
mentioned, the poor oral bio availability of catecholamines has prevented
their clinical use as orally administered drugs.

[0009] Alternatively, the oral mucosal delivery of drugs utilizes
primarily the sublingual and buccal mucosas as absorption sites, although
the whole oral cavity can be considered for both mucosal (local effect)
and trans-mucosal (systemic effect) absorption of drugs. Owing to the
ease of administration, the oral cavity is an attractive site for
delivery of drugs. Furthermore, the oral cavity has reduced enzymatic
activity as compared to the intestinal, rectal, and nasal mucosas, which
may lead to an improved absorption and a reduced irritation at this site
of absorption. The oral cavity is less sensitive to damage and irritation
than the nasal epithelium.

[0010] The oral mucosa provides a protective coating for underlying
tissues while acting as a barrier to microorganisms and as a control to
the passage of substances through the oral cavity. In humans, the buccal
membranes consist of keratinized and nonkeratinized striated epithelium.
Many factors, including partition characteristics, degree of ionization,
and molecular size, influence the transport of drugs across the membrane.
However, many drugs do not pass through the buccal membranes in
sufficient amounts to be useful.

[0012] Due to high buccal vascularity, buccally delivered drugs can gain
direct access to the systemic circulation and are not subject to
first-pass hepatic metabolism. In addition, therapeutic agents
administered via the buccal route are not exposed to the environment of
the gastrointestinal tract (Mitra et al., Encyclopedia of Pharm. Tech.
2002, 2081-2095). Further, the buccal mucosa has low enzymatic activity
relative to the nasal and rectal routes. Thus, the potential for drug
inactivation due to biochemical degradation is less rapid and extensive
than other administration routes (de Varies et al., Crit. Rev. Ther. Drug
Carr. Syst. 1999, 8, 271-303).

[0013] Since the oral mucosa is renewed relatively fast, discoloration of
the oral cavity is minimized with buccal delivery as compared to other
modes of delivery. Buccal delivery is also advantageous over other modes
of delivery. For example, local skin irritations are observed with the
transdermal delivery of catecholamines. Further, irritation at the
injection site and precipitation of decomposed apomorphine are sometimes
associated with its intermittent subcutaneous administration as well as
with delivery via continuous infusion.

[0014] To this end, the inventors have discovered methods to administer
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol and related compounds via oral mucosa delivery. This has been
achieved by the development of novel pharmaceutical compositions of said
compounds for buccal administration in the treatment of Parkinson's
disease as well as the other conditions disclosed in this application.
Accordingly, the present invention provides pharmaceutical compositions
for buccal administration comprising one of the compounds of the
invention, or a pharmaceutically acceptable salt, and a pharmaceutically
acceptable carrier.

[0015] Separately, the nasal mucosa offers an alternative to oral and
parenteral administration; intranasal administration is a practical way
to achieve the therapeutic effect of many medications. Advantages of this
method are that drugs can be administered readily and simply, and either
a localized or a systemic effect can be achieved. In nasal
administration, the biologically active substance must be applied to the
nasal mucosa in such a condition that it is able to penetrate or be
absorbed through the mucosa. The extensive network of blood capillaries
under the nasal mucosa is particularly suited to provide a rapid and
effective systemic absorption of drugs. Moreover, the nasal epithelial
membrane consists of practically a single layer of epithelial cells
(pseudostratified epithelium) and may be more suited for drug
administration than other mucosal surfaces having squamous epithelial
layers, such as the mouth, vagina, etc.

[0016] Further, the intranasal administration of drugs that exert their
effect in the brain may have the advantage in that the
blood-brain-barrier (BBB) may be a less of a hurdle for the drug than if
the drug had to traverse the BBB through the `normal` blood stream. The
onset of action may also be significantly faster for the intranasal
administration of CNS based drugs than by other routes of administration.

[0017] The inventors have discovered methods to administer
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol and related compounds via intranasal administration. This has been
achieved by the development of novel pharmaceutical compositions of said
compounds for intranasal administration in the treatment of Parkinson's
disease as well as the other conditions disclosed in this application.
Accordingly, the present invention provides pharmaceutical compositions
for intranasal administration comprising one of the compounds of the
invention, or a pharmaceutically acceptable salt, and a pharmaceutically
acceptable carrier.

[0018] Moreover, delivering pharmaceutical agents into the systemic
circulation through the skin is seen as a desirable route of
administration while providing several other advantages over oral
administration. For example, bypassing the gastrointestinal (GI) tract
would obviate the GI irritation that frequently occurs and avoid partial
first-pass inactivation by the liver. Further, steady absorption of drug
over hours or days can be preferable to the blood level spikes and
troughs produced by oral dosage forms. Additionally, patients often
forget to take their medicine and even the most faithfully compliant get
tired of swallowing pills, especially if they must take several each day.
The transdermal route can also be more effective than the oral route in
that it can provide for relatively faster or slower (extended) absorption
and onset of therapeutic action.

[0019] Transdermal delivery also poses inherent challenges, in part
because of the nature of skin. Skin is essentially a thick membrane that
protects the body by acting as a barrier. Consequently, the movement of
drugs or any external agent through the skin is a complex process. The
structure of skin includes the relatively thin epidermis, or outer layer,
and a thicker inner layer called the dermis. For a drug to penetrate
unbroken skin, it must first move into and through the stratum corneum,
which is the outer layer of the epidermis. Then the drug must penetrate
the viable epidermis, papillary dermis, and capillary walls to enter the
blood stream or lymph channels. Each tissue features a different
resistance to penetration, but the stratum corneum is the strongest
barrier to the absorption of transdermal and topical drugs. The tightly
packed cells of the stratum corneum are filled with keratin. The
keratinization and density of the cells may be responsible for skin's
impermeability to certain drugs.

[0020] In recent years, advances in transdermal delivery include the
formulation of permeation enhancers (skin penetration enhancing agents).
Permeation enhancers often are lipophilic chemicals that readily move
into the stratum corneum and enhance the movement of drugs through the
skin. Non-chemical modes also have emerged to improve transdermal
delivery; these include ultrasound, iontophoresis, and electroporation.

[0021] The inventors have discovered methods to administer
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol and related compounds via transdermal delivery. This has been
achieved by the development of novel pharmaceutical compositions of said
compounds for transdermal administration in the treatment of Parkinson's
disease as well as the other conditions disclosed in this application.
Accordingly, the present invention provides pharmaceutical compositions
for transdermal administration comprising one of the compounds of the
invention, or a pharmaceutically acceptable salt, and a pharmaceutically
acceptable carrier.

SUMMARY OF THE INVENTION

[0022] The present invention relates a pharmaceutical composition for
delivery across the oral mucosa, nasal mucosa or skin comprising
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

[0023] Another aspect relates to a use of a pharmaceutical composition for
delivery across the oral mucosa, nasal mucosa or skin comprising
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol or a pharmaceutically acceptable salt thereof, in the preparation of
a medicament for the treatment of Parkinson's disease.

[0024] Further, aspects of the present invention relate to a
pharmaceutical composition for delivery across the oral mucosa comprising
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier. A separate aspect is directed to a
pharmaceutical composition for delivery across the oral mucosa comprising
racemic trans-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline--
6,7-diol or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

[0025] Another aspect relates to a method for the delivery across the oral
mucosa of the (4aR,10aR) enantiomer or the racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof. Separately, an aspect of the
invention relates to the use of a pharmaceutical composition for delivery
across the oral mucosa comprising a therapeutically effective amount of
the (4aR,10aR) enantiomer or the racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for treating a neurological disorder. In one aspect, the
neurological disorder is Parkinson's disease.

[0026] A separate concern of the invention is directed to a method of
treating a neurological disorder comprising administering a
pharmaceutical composition for delivery across the oral mucosa of a
therapeutically effective amount of the (4aR,10aR) enantiomer or the
racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof. In one aspect, the neurological
disorder is Parkinson's disease.

[0027] Yet another aspect of the present invention relates to a
pharmaceutical composition for intranasal administration comprising
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier. A separate aspect is directed to a
pharmaceutical composition for intranasal administration comprising
racemic trans-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline--
6,7-diol or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

[0028] Another aspect relates to a method for the intranasal delivery of
the (4aR,10aR) enantiomer or the racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof. Separately, an aspect of the
invention relates to the use of a pharmaceutical composition for
intranasal administration comprising a therapeutically effective amount
of the (4aR,10aR) enantiomer or racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for treating a neurological disorder. In one aspect, the
neurological disorder is Parkinson's disease.

[0029] A separate concern of the invention is directed to a method of
treating a neurological disorder comprising administering a
pharmaceutical composition for intranasal administration of a
therapeutically effective amount of the (4aR,10aR) enantiomer or the
racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof. In one aspect, the neurological
disorder is Parkinson's disease.

[0030] One aspect of the present invention relates to a pharmaceutical
composition for transdermal delivery comprising
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier. A separate aspect is directed to a
pharmaceutical composition for transdermal delivery comprising racemic
trans-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol
or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.

[0031] Another aspect relates to a method for a pharmaceutical composition
for transdermal delivery comprising the (4aR,10aR) enantiomer or the
racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof. Separately, an aspect of the
invention relates to the use of a pharmaceutical composition for
transdermal delivery comprising a therapeutically effective amount of the
(4aR,10aR) enantiomer or the racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for treating a neurological disorder. In one aspect, the
neurological disorder is Parkinson's disease.

[0032] A separate concern of the invention relates to a method of treating
a neurological disorder comprising administering a pharmaceutical
composition for transdermal delivery of a therapeutically effective
amount of the (4aR,10aR) enantiomer or the racemic trans isomer of
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol or a
pharmaceutically acceptable salt thereof. In one aspect, the neurological
disorder is Parkinson's disease.

[0033] Yet another aspect relates to a pharmaceutical composition for
delivery across the oral mucosa, nasal mucosa or skin comprising a
compound selected from Formula 1a, 1b or 1c:

##STR00001##

wherein each Rx, Ry, and Rz is independently C1-6
alkanoyl, cycloalkylalkyl, phenylacetyl or benzoyl, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0034] One aspect of the invention is directed to a ratio from about 0:1
to about 1:0 of a mixture of the asymmetric diesters of Formula Ia
wherein Rx≠Ry. A separate aspect of the invention relates to a
ratio from about 0:1 to about 1:0 of a mixture of the mono-esters of
Formulas Ib and Ic.

[0035] Separate aspects of the invention are directed to the uses and
methods of the pharmaceutical compositions described above for the
treatment of Parkinson's disease.

DETAILED DESCRIPTION

[0036] The compounds of the present invention contain two chiral centers
(denoted with * in the below formula)

##STR00002##

[0037] The compounds of the invention can exist in two different
diastereomeric forms, the cis- and trans-isomers, both of which can exist
in two enantiomeric forms. The present invention relates only to the
trans racemate and the (4aR,10aR)-enantiomer.

##STR00003## ##STR00004##

[0038] As previously indicated, the present invention is based on the
discovery that
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol (herein referred to as "Compound 10") is a potent D1/D2 agonist
which is bioavailable via delivery through the oral mucosa. The invention
is explained in greater detail below but this description is not intended
to be a detailed catalog of all the different ways in which the invention
may be implemented, or all the features that may be added to the instant
invention.

[0039] Racemic
trans-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol
is a 1:1 mixture of
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol and (4aS,10aS)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quin-
oline-6,7-diol.

[0040] "Related compounds of
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol" refer to racemic
trans-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol-
s and the symmetric, asymmetric and mono-esters of Formulas Ia, Ib and Ic.
Both the racemic trans isomer and the (4aR,10aR)-enantiomer of Formulas
Ia, Ib and Ic fall within the scope of the invention.

[0041] As used herein, "C1-6 alkanoyl" refers to a straight-chain or
branched-chain alkanoyl group containing from one to six carbon atoms,
examples of which include a formyl group, an acetyl group, a pivaloyl
group, and the like.

[0042] "Cycloalkylalkyl" refers to a saturated carbocyclic ring attached
to a terminal end of an a straight-chain or branched-chain alkylene
linker containing one to three carbon atoms, examples of which include a
cyclopropylmethyl group, a cyclobutylethyl group, a cyclopentylpropyl
group, and the like.

[0043] As used herein, "active ingredient" or the "compound of the
invention" refers to a compound selected from the group consisting of
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol; racemic trans
1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol; or a
compound of Formulas Ia, Ib or Ic. Both the racemic trans isomer and the
(4aR,10aR)-enantiomer of Formulas Ia, Ib and Ic fall within the scope of
the invention.

A. Administration Across the Oral Mucosa

[0044] As used herein, the "oral mucosal" membranes of the buccal cavity
encompass the following five regions: the buccal mucosa (cheeks), the
floor of the mouth (sublingual), the gums (gingiva), the palatal mucosa,
and the lining of the lips.

[0045] The pharmaceutical compositions described herein may contain
permeation enhancers because the buccal cavity is a poor absorptive site
of the alimentary tract. The buccal cavity lacks the typical villus-type
of absorptive membrane of the intestine. Further, unlike the intestine,
the junction between epithelial cells are tight. For a substance to be
absorbed through the mucosal membrane of the buccal cavity, it should be
presented in a lipophilic form.

[0048] The carriers and excipients include ion-exchange microspheres which
carry suitable anionic groups such as carboxylic acid residues,
carboxymethyl groups, sulphopropyl groups and methylsulphonate groups.
Ion-exchange resins, such as cation exchangers, can also be used.
Chitosan, which is partially deacetylated chitin, or
poly-N-acetyl-D-glucosamine, or a pharmaceutically acceptable salt
thereof such as hydrochloride, lactate, glutamate, maleate, acetate,
formate, propionate, maleate, malonate, adipate, or succinate. Suitable
other ingredients for use as non-ion-exchange microspheres include
starch, gelatin, collagen and albumin.

pH Adjustment

[0049] Excipients to adjust the tonicity of the composition may be added
such as sodium chloride, glucose, dextrose, mannitol, sorbitol, lactose,
and the like. Acidic or basic buffers can also be added to the oral
mucosal composition to control the pH. Low pH may be preferable in the
instant case.

[0050] The compound of the invention as a pharmaceutical composition, may
be administered in any suitable way in the oral cavity, and the compound
may be presented in any suitable dosage form for such administration,
e.g. in form of simple solutions or dispersions, simple tablets, matrix
tablets, capsules, powders, syrups, dissolvable films, patches,
lipophilic gels. In one embodiment, the compound of the invention is
administered in the form of a solid pharmaceutical entity, suitably as a
tablet or a capsule. In another particular embodiment, the compound of
the invention is administered in the form of a dissolvable film.

[0051] In the case of oral mucosal administration of the compound of the
invention, conventional dosage forms may not be able to assure
therapeutic drug levels in because of physiological removal mechanism of
the oral cavity (washing effect of saliva and mechanical stress), which
remove the drug formulation away from the oral mucosa, resulting in too
short exposure time and unpredictable absorption. To obtain the desired
therapeutic action it may therefore be necessary to prolong and improve
the contact between the compound of the invention and the mucosa. To
fulfill the therapeutic requirement, formulations designed for sublingual
or buccal administration may therefore contain mucoadhesive agents to
maintain an intimate and prolonged contact of the formulation with the
absorption site; penetration enhancers, to improve drug permeation across
the mucosa; and enzyme inhibitors to eventually protect the drug from
degradation by means of oral mucosal enzymes.

[0052] In one embodiment, the delivery across the oral mucosa occurs
through buccal route. In another embodiment, the delivery across the oral
mucosa occurs through the sublingual route. In another embodiment, the
delivery across the oral mucosa occurs through the lips. In one
embodiment, the pharmaceutical composition is a liquid solution. In one
embodiment, the pharmaceutical composition is a gel. In yet another
embodiment, the composition further comprises a penetration enhancer. In
yet another embodiment, the composition is a tablet. In yet another
embodiment, the composition is a lozenge. In yet another embodiment, the
composition is a chewing gum. In yet another embodiment, the composition
is a lipstick.

[0053] Methods for the preparation of solid pharmaceutical compositions
are also well known in the art. Tablets may thus be prepared by mixing
the active ingredient with ordinary adjuvants, fillers and diluents and
subsequently compressing the mixture in a convenient tabletting machine.
Examples of adjuvants, fillers and diluents comprise microcrystalline
cellulose, corn starch, potato starch, lactose, mannitol, sorbitol
talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any
other adjuvant or additive such as colorings, aroma, preservatives, etc.
may also be used provided that they are compatible with the active
ingredients.

[0054] In particular, the tablet formulations according to the invention
may be prepared by direct compression of the compound of the invention
with conventional adjuvants or diluents. Alternatively, a wet granulate
or a melt granulate of the compound of the invention, optionally in
admixture with conventional adjuvants or diluents may be used for
compression of tablets.

[0055] In a specific embodiment of the invention there is provided a
pharmaceutical composition comprising a therapeutically effective amount
of the compound of the invention, or a pharmaceutically acceptable acid
addition salt thereof for administration via the oral mucosa, in
particular buccally or sublingually.

[0056] Manufacturing processes for buccal and sublingual disintegrating
tablets are known in the art and include, but are not limited to,
conventional tableting techniques, freeze-dried technology, and
floss-based tableting technology.

Conventional Tableting Techniques

[0057] Conventional tablet processing features conventional tablet
characteristics for ease of handling, packaging, and fast disintegration
(Ghosh and Pfister, Drug Delivery to the Oral Cavity: Molecule to Market,
2005, New York, CRC Press). The technology is based on a combination of
physically modified polysaccharides that have water dissolution
characteristics that facilitate fast disintegration and high
compressibility. The result is a fast-disintegrating tablet that has
adequate hardness for packaging in bottles and easy handling.

[0058] In certain embodiments, the manufacturing process involves
granulating low-moldable sugars (e.g., mannitol, lactose, glucose,
sucrose, and erythritol) that show quick dissolution characteristics with
high-moldable sugars (e.g., maltose, sorbitol, trehalose, and maltitol).
The result is a mixture of excipients that have fast-dissolving and
highly moldable characteristics (Hamilton et al., Drug Deliv. Technol.
2005, 5, 34-37). The compound of the invention can be added, along with
other standard tableting excipients, during the granulation or blending
processes. The tablets are manufactured at a low compression force
followed by an optional humidity conditioning treatment to increase
tablet hardness (Parakh et al., Pharm. Tech. 2003, 27, 92-100).

[0059] In other embodiments, a compressed buccal or sublingual tablet
comprising the compound of the invention is based on a conventional
tableting process involving the direct compression of active ingredients,
effervescent excipients, and taste-masking agents (see U.S. Pat. No.
5,223,614). The tablet quickly disintegrates because effervescent carbon
dioxide is produced upon contact with moisture. The effervescent
excipient (known as effervescence couple) is prepared by coating the
organic acid crystals using a stoichiometrically lesser amount of base
material. The particle size of the organic acid crystals is carefully
chosen to be larger than the base excipient to ensure uniform coating of
the base excipient onto the acid crystals. The coating process is
initiated by the addition of a reaction initiator, which is purified
water in this case. The reaction is allowed to proceed only to the extent
of completing the base coating on organic acid crystals. The required
end-point for reaction termination is determined by measuring carbon
dioxide evolution. Then, the excipient is mixed with the active
ingredient or active microparticles and with other standard tableting
excipients and then compressed into tablets.

[0060] In still other embodiments, the buccal or sublingual tablets are
made by combining non-compressible fillers with a taste-masking excipient
and active ingredient into a dry blend. The blend is compressed into
tablets using a conventional rotary tablet press. Tablets made with this
process have higher mechanical strength and are sufficiently robust to be
packaged in blister packs or bottles (Aurora et al., Drug Deliv. Technol.
2005, 5:50-54). In other embodiments, the method further incorporates
taste-masking sweeteners and flavoring agents such as mint, cherry, and
orange. In certain embodiments, the compound of the invention tablets
made with this process should disintegrate in the mouth in 5-45 seconds
and can be formulated to be bio equivalent to intramuscular or
subcutaneous dosage forms containing the compound of the invention.

Freeze-Dried Buccal or Sublingual Tablets

[0061] The freeze-drying process involves the removal of water (by
sublimation upon freeze drying) from the liquid mixture of the compound
of the invention matrix former, and other excipients filled into
preformed blister pockets. The formed matrix structure is very porous in
nature and rapidly dissolves or disintegrates upon contact with saliva
(Sastry et al., Drug Delivery to the Oral Cavity Molecule to Market,
2005, New York, CRC Press, pp. 311-316).

[0062] Common matrix-forming agents include gelatins, dextrans, or
alginates which form glassy amorphous mixtures for providing structural
strength; saccharides such as mannitol or sorbitol for imparting
crystallinity and hardness; and water, which functions as a manufacturing
process medium during the freeze-drying step to induce the porous
structure upon sublimation. In addition, the matrix may contain
taste-masking agents such as sweeteners, flavorants, pH-adjusting agents
such as citric acid, and preservatives to ensure the aqueous stability of
the suspended drug in media before sublimation.

[0063] In this embodiment, freeze-dried buccal or sublingual Oral
Disintegrating Tablets (herein referred to as ODTs) comprising the
compound of the invention can be manufactured and packaged in polyvinyl
chloride or polyvinylidene chloride plastic packs, or they may be packed
into laminates or aluminum multilaminate foil pouches to protect the
product from external moisture.

[0064] Other known methods for manufacturing buccal or sublingual ODTs
include lyophilization (e.g., Lyoc (Farmalyoc, now Cephalon, Franzer,
Pa.) and QuickSolv (Janssen Pharmaceutica, Beerse, Belgium). Lyoc is a
porous, solid wafer manufactured by lyophilizing an oil-in-water emulsion
placed directly in a blister and subsequently sealed. The wafer can
accommodate high drug dosing and disintegrates rapidly but has poor
mechanical strength (see EP 0159237). QuickSolv tablets are made with a
similar technology that creates a porous solid matrix by freezing an
aqueous dispersion or solution of the matrix formulation. The process
works by removing water using an excess of alcohol (solvent extraction).
In certain embodiments, the manufacturing methods which utilize the
lyophilization techniques, such as those related to QuickSolv as
described above, could be of particular importance for producing buccal
or sublingual ODTs comprising the compound of the invention. This is
especially so in light of the data provided herein which shows the
potential negative effect that highly water soluble excipients can have
in the absorption of the compound of the invention in vivo. Thus, a
buccal or sublingual ODT comprising the compound of the invention
manufactured by such a lyophilization technique could provide increased
in vivo absorption due of the removal of water soluble excipients
occurring during the water removal step as described above.

Floss-Based Buccal or Sublingual Tablets

[0065] In other embodiments, floss-based tablet technology (e.g.,
FlashDose, Biovail, Mississauga, ON, Canada) can be used to produce
fast-dissolving buccal or sublingual tablets comprising the compound of
the invention using a floss known as the shearform matrix. This floss is
commonly composed of saccharides such as sucrose, dextrose, lactose, and
fructose. The saccharides are converted into floss by the simultaneous
action of flash-melting and centrifugal force in a heat-processing
machine similar to that used to make cotton candy. See U.S. Pat. Nos.
5,587,172, 5,622,717, 5,567,439, 5,871,781, 5,654,003, and 5,622,716. The
fibers produced are usually amorphous in nature and are partially
re-crystallized, which results in a free-flowing floss. The floss can be
mixed with the compound of the invention and pharmaceutically acceptable
excipients followed by compression into a tablet that has fast-dissolving
characteristics.

Sublingual Tablets

[0066] Additional techniques can also be used to formulate the rapidly
disintegrating or dissolving buccal or sublingual tablets of the present
invention (Sastry et al., Pharm. Sci. Tech. Today 2000, 3: 138-145; Chang
et al., Pharmaceutical Technology 2000, 24: 52-58; Sharma et al.,
Pharmaceutical Technology North America 2003, 10-15; Allen, International
Journal of Pharmaceutical Technology 2003, 7, 449-450; Dobetti,
Pharmaceutical Technology Europe 2000, 12: 32-42; and Verma and Garg,
Pharmaceutical Technology On-Line 2001, 25, 1-14). Direct compression,
one of these techniques, requires the incorporation of a super
disintegrant into the formulation, or the use of highly water soluble
excipients to achieve fast tablet disintegration or dissolution. Direct
compression does not require the use of moisture or heat during tablet
formation process, so it is very useful for the formulation and
compression of tablets containing moisture-labile and heat-labile
medications. However, the direct compression method is very sensitive to
changes in the types and proportions of excipients, and in the
compression force (CF), when used to achieve tablets of suitable hardness
without compromising the rapid disintegration capabilities. As will be
appreciated by one of skill in the art, in order for tablets administered
sublingually to release the dose of medication for maximum rate and
extent of absorption, the tablet must disintegrate almost instantaneously
following insertion into the sublingual cavity. Precise selection and
evaluation of the type and proportion of excipients used to formulate the
tablet control the extent of hardness and rate of disintegration.
Compression force (CF) can also be adjusted to result in tablets that
have lower hardness (H) and disintegrate more quickly. Unique packaging
methods such as strip packaging may be required to compensate for the
problem of extreme friability of rapidly disintegrating, direct
compression tablets.

[0068] In a further aspect the invention provides the use of said
composition for the preparation of a medicament for the treatment of
neurodegenerative disorders such as Parkinson's disease and Huntington's
disease.

[0069] In a further aspect the invention provides the use of the
pharmaceutical composition for the preparation of a medicament for the
treatment of psychoses, impotence, renal failure, heart failure or
hypertension.

[0070] In another aspect the invention provides the use of the
pharmaceutical composition for the manufacture of a medicament for the
treatment of cognitive impairment in a mammal.

[0071] In a still further aspect the invention provides the use of the
pharmaceutical composition for the manufacture of a medicament for the
treatment of restless legs syndrome (RLS) or periodic limb movement
disorder (PLMD).

[0072] In a still further aspect the invention provides the use of the
pharmaceutical composition for the manufacture of a medicament for the
treatment of erectile dysfunction.

[0073] In a different aspect the invention provides the use of the
pharmaceutical composition for the manufacture of a medicament for the
treatment of movement disorders, poverty of movement, dyskinetic
disorders, gait disorders or intention tremor in a mammal.

[0074] In a further aspect the invention provides the use of the
pharmaceutical composition for the treatment of neurodegenerative
disorders such as Parkinson's disease and Huntington's disease.

[0075] In a further aspect the invention provides the use of the
pharmaceutical composition for the treatment of psychoses, impotence,
renal failure, heart failure or hypertension.

[0076] In another aspect the invention provides the use of the
pharmaceutical composition for the treatment of cognitive impairment in a
mammal.

[0077] In a still further aspect the invention provides the use of the
pharmaceutical composition for the treatment of restless legs syndrome
(RLS) or periodic limb movement disorder (PLMD).

[0078] In a different aspect the invention provides the use of the
pharmaceutical composition for the treatment of movement disorders,
poverty of movement, dyskinetic disorders, gait disorders or intention
tremor in a mammal.

[0079] In separate aspects the invention provides the use of the
pharmaceutical composition for the manufacture of medicaments, which are
intended for administration via the oral mucosa.

[0080] The invention also provides a method of treating a mammal suffering
from a neurodegenerative disorder such as Parkinson's disease and
Huntington's disease comprising administering to the mammal a
therapeutically effective amount of the pharmaceutical composition.

[0081] In another aspect the invention also provides a method of treating
a mammal suffering from psychoses, impotence, renal failure, heart
failure or hypertension, comprising administering to the mammal a
therapeutically effective amount of the pharmaceutical composition.

[0082] In a further aspect the invention provides a method of treating a
mammal suffering from a cognitive impairment, comprising administering to
the mammal an effective amount of the pharmaceutical composition.

[0083] The invention also relates to a method of treating a mammal
suffering from restless legs syndrome (RLS) or periodic limb movement
disorder (PLMD), comprising administering to the mammal a therapeutically
effective amount of the compound of the invention, or a pharmaceutically
acceptable addition salt thereof.

[0084] The invention also relates in a separate aspect to a method of
treating a mammal suffering from movement disorders, poverty of movement,
dyskinetic disorders, gait disorders or intention tremor comprising
administering to the mammal of the pharmaceutical composition.

[0085] The therapeutically effective amount of the compound of the
invention, calculated as the daily dose of the compound of the invention
above as the free base, is suitably between 0.001 and 12.5 mg/day, more
suitable between 0.005 and 10.0 mg/day, e.g. preferably between 0.01 and
5.0 mg/day. In a specific embodiment the daily dose of the compound of
the invention is between 0.1 and 1.0 mg/day.

[0086] In another embodiment the daily dose of the compound of the
invention is less than about 0.1 mg/day. In a separate embodiment the
daily dose of the compound of the invention is about 0.01 mg/day. In a
further embodiment the invention provides a formulation comprising from
0.0001 mg to 12.5 mg of the compound of the invention for delivery via
the oral mucosa. In a further embodiment the invention provides a
formulation comprising from 0.0001 mg to 0.01 mg of the compound of the
invention for delivery via the oral mucosa. In a further embodiment the
invention provides a formulation comprising from 0.001 mg to 0.10 mg of
the compound of the invention for delivery via the oral mucosa. In a
further embodiment the invention provides a formulation comprising from
0.01 mg to 1.0 mg of the compound of the invention for delivery via the
oral mucosa.

[0087] In yet other embodiments, the invention described herein provides
pharmaceutical tablets for buccal or sublingual administration comprising
the compound of the invention wherein the administration of the
pharmaceutical tablets provides a pharmacokinetic profile substantially
equivalent to the pharmacokinetic profile of traditional injectable
dosage forms comprising the compound of the invention administered either
subcutaneously or intramuscularly. In certain embodiments, the
pharmaceutical tablets for buccal or sublingual administration described
herein can provide a pharmacokinetic profile substantially equivalent to
the pharmacokinetic profile of traditional injectable dosage forms
comprising the compound of the invention administered either
subcutaneously or intramuscularly, wherein the pharmacokinetic profile
consists of one or more of the pharmacokinetic parameters selected from
the group consisting of: Cmax, Tmaχ, AUC.sub.(last), and
AUC.sub.(0-∞).

[0088] Ultimately, the exact dose of the compound of the invention and the
particular formulation to be administered depend on a number of factors,
e.g., the condition to be treated, the desired duration of the treatment
and the rate of release of the active agent. For example, the amount of
the active agent required and the release rate thereof may be determined
on the basis of known in vitro or in vivo techniques, determining how
long a particular active agent concentration in the blood plasma remains
at an acceptable level for a therapeutic effect.

B. Intranasal Administration

[0089] The term "intranasal delivery" as used herein means a method for
drug absorption through and within the nasal mucosa.

[0090] Carriers" or "vehicles" as used herein refer to carrier materials
suitable for intranasal drug administration, and include any such
materials known in the art, e.g., any liquid, gel, solvent, liquid
diluent, solubilizer, or the like, which is non toxic and which does not
interact with other components of the composition in a deleterious
manner. Examples of suitable vehicles for use herein include water,
alcohols such as isopropyl alcohol and isobutyl alcohol, polyalcohol such
as glycerol, and glycols such as propylene glycol, and esters of such
polyols, (e.g., mono-, di-, or tri-glycerides).

Intranasal Compositions

[0091] Relative to an oral dosage form such as a tablet or capsule,
intranasal delivery provides for rapid absorption, faster onset of
therapeutic action and avoidance of gut wall or liver first pass
metabolism. For patients who have difficulty in swallowing tablets,
capsules or other solids or those who have intestinal failure, the
intranasal delivery route may be preferred.

[0092] The compositions for nasal administration include the compound of
the invention, or a pharmaceutically acceptable salt thereof, and
optionally can also include other ingredients including, but not limited
to, carriers and excipients, such as absorption-promoting agents which
promote nasal absorption of the active ingredient after nasal
administration. Other optional excipients include diluents, binders,
lubricants, glidants, disintegrants, desensitizing agents, emulsifiers,
mucosal adhesives, solubilizers, suspension agents, viscosity modifiers,
ionic tonicity agents, buffers, carriers, flavors and mixtures thereof.

[0093] The amount of drug absorbed depends on many factors. These factors
include the drug concentration, the drug delivery vehicle, mucosal
contact time, the venous drainage of the mucosal tissues, the degree that
the drug is ionized at the pH of the absorption site, the size of the
drug molecule, and its relative lipid solubility. Those of skill in the
art can readily prepare an appropriate intranasal composition, which
delivers an appropriate amount of the active agent, taking these factors
into consideration.

Absorption Promoting Agents

[0094] The transport of the active ingredient across normal nasal mucosa
can be enhanced by optionally combining it with an absorption promoting
agent, such as those disclosed in U.S. Pat. Nos. 5,629,011, 5,023,252,
6,200,591, 6,369,058, 6,380,175, and International Publication Number WO
01/60325. Examples of these absorption promoting agents include, but are
not limited to, cationic polymers, surface active agents, chelating
agents, mucolytic agents, cyclodextrin, polymeric hydrogels, combinations
thereof, and any other similar absorption promoting agents known to those
of skill in the art. Representative absorption promoting excipients
include phospholipids, such as phosphatidylglycerol or
phosphatidylcholine, lysophosphatidyl derivatives, such as
lysophosphatidylethanolamine, lysophosphatidylcholine,
lysophosphatidylglycerol, lysophosphatidylserine, or lysophosphatidic
acid, polyols, such as glycerol or propylene glycol, fatty acid esters
thereof such as glycerides, amino acids, and esters thereof, and
cyclodextrins. Gelling excipients or viscosity-increasing excipients can
also be used.

Mucoadhesive/Bioadhesive Polymers

[0095] The transport of the active ingredient across normal mucosal
surfaces can also be enhanced by increasing the time in which the
formulations adhere to the mucosal surfaces. Mucoadhesive/bioadhesive
polymers, for example, those which form hydrogels, exhibit mucoadhesion
and controlled drug release properties and can be included in the
intranasal compositions described herein. Examples of such formulations
are disclosed in U.S. Pat. Nos. 6,068,852 and 5,814,329; and
International Publication Number WO99/58110. Representative bioadhesive
or hydrogel-forming polymers capable of binding to the nasal mucosa are
well known to those of skill in the art, and include polycarbophil,
polylysine, methylcellulose, sodium carboxymethylcellulose,
hydroxypropyl-methylcellulose, hydroxyethyl cellulose, pectin, Carbopol
934P, polyethylene oxide 600K, Pluronic F127, polyisobutylene (PIB),
polyisoprene (PIP), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA),
xanthum gum, guar gum, and locust bean gum.

[0096] Other nasal delivery compositions are chitosan-based and are
suitable to increase the residence time of the active ingredient on
mucosal surfaces, which results in increasing its bioavailability.
Examples of these nasal delivery compositions are disclosed in U.S. Pat.
Nos. 6,465,626, 6,432,440, 6,391,318, and 5,840,341; European Patent
Numbers EP0993483 and EP1051190; and International Publication Numbers WO
96/05810, WO 96/03142, and WO 93/15737. Additionally, the present
invention can be formulated with powder microsphere and mucoadhesive
compositions as disclosed in European Patent Numbers EP1025859 and
EP1108423, which are incorporated herein by reference with regard to such
composition.

[0097] Finally, thiolated polymeric excipients that form covalent bonds
with the cysteine-rich subdomains of the mucus membrane can also provide
mucoadhesion, which prolongs the contact time between the active
ingredient and the membrane. Such excipients are disclosed in
International Publication Number WO 03/020771.

[0099] The carriers and excipients include ion-exchange microspheres which
carry suitable anionic groups such as carboxylic acid residues,
carboxymethyl groups, sulphopropyl groups and methylsulphonate groups.
Ion-exchange resins, such as cation exchangers, can also be used.
Chitosan, which is partially deacetylated chitin, or
poly-N-acetyl-D-glucosamine, or a pharmaceutically acceptable salt
thereof such as hydrochloride, lactate, glutamate, maleate, acetate,
formate, propionate, maleate, malonate, adipate, or succinate. Suitable
other ingredients for use as non-ion-exchange microspheres include
starch, gelatin, collagen and albumin.

[0101] Excipients to adjust the tonicity of the composition may be added
such as sodium chloride, glucose, dextrose, mannitol, sorbitol, lactose,
and the like. Acidic or basic buffers can also be added to the intranasal
composition to control the pH.

Incorporation of the Active Agent into the Compositions

[0102] In addition to using absorption enhancing agents, which increase
the transport of the active agents through the mucosa, and bioadhesive
materials, which prolong the contact time of the active agent along the
mucosa, the administration of the active agent can be controlled by using
controlled release formulations, which can provide rapid or sustained
release, or both, depending on the formulations.

[0103] There are numerous particulate drug delivery vehicles known to
those of skill in the art which can include the active ingredients, and
deliver them in a controlled manner. Examples include particulate
polymeric drug delivery vehicles, for example, biodegradable polymers,
and particles formed of non-polymeric components. These particulate drug
delivery vehicles can be in the form of powders, microparticles,
nanoparticles, microcapsules, liposomes, and the like. Typically, if the
active agent is in particulate form without added components, its release
rate depends on the release of the active agent itself. Typically, the
rate of absorption is enhanced by presenting the drug in a micronized
form, wherein particles are below 20 microns in diameter. In contrast, if
the active agent is in particulate form as a blend of the active agent
and a polymer, the release of the active agent is controlled, at least in
part, by the removal of the polymer, typically by dissolution,
biodegradation, or diffusion from the polymer matrix.

[0104] The compositions can provide an initial rapid release of the active
ingredient followed by a sustained release of the active ingredient. U.S.
Pat. No. 5,629,011 provides examples of this type of formulation and is
incorporated herein by reference with regard to such formulations.

[0105] There are numerous compositions that utilize intranasal delivery
and related methods thereof. Moreover, there are numerous methods and
related delivery vehicles that provide for intranasal delivery of various
pharmaceutical compositions. For example, intranasal compositions that
employ current marketed nicotine replacement therapies (See, N. J.
Benowitz, Drugs, 45: 157-170 (1993) are also suitable for administering
the compounds described herein.

Nasal Insufflator Devices

[0106] The intranasal compositions can be administered by any appropriate
method according to their form. A composition including microspheres or a
powder can be administered using a nasal insufflator device. Examples of
these devices are well known to those of skill in the art, and include
commercial powder systems such as Fisons Lomudal System. An insufflator
produces a finely divided cloud of the dry powder or microspheres. The
insufflator is preferably provided with a mechanism to ensure
administration of a substantially fixed amount of the composition. The
powder or microspheres can be used directly with an insufflator, which is
provided with a bottle or container for the powder or microspheres.
Alternatively, the powder or microspheres can be filled into a capsule
such as a gelatin capsule, or other single dose device adapted for nasal
administration. The insufflator preferably has a mechanism to break open
the capsule or other device.

[0107] Further, the composition can provide an initial rapid release of
the active ingredient followed by a sustained release of the active
ingredient, for example, by providing more than one type of microsphere
or powder.

Use of Metered Sprays

[0108] Intranasal delivery can also be accomplished by including the
active ingredient in a solution or dispersion in an aqueous medium which
can be administered as a spray. Appropriate devices for administering
such a spray include metered dose aerosol valves and metered dose pumps,
optionally using gas or liquid propellants.

[0110] In addition to the foregoing, the compounds and intranasal
compositions including the compounds can also be administered in the form
of nose-drops, sprays, irrigations, and douches, as is known in the art.
Nose drops are typically administered by inserting drops while lying on a
bed, with the patient on his or her back, especially with the head lying
over the side of the bed. This approach helps the drops get farther back.

[0111] Nasal irrigation involves regularly flooding the nasal cavity with
warm salty water, which includes one or more compounds as described
herein, or their pharmaceutically acceptable salts. Nasal douches are
typically used by filling a nasal douche with a salt solution including
one or more compounds as described herein, or their pharmaceutically
acceptable salts, inserting the nozzle from the douche into one nostril,
opening one's mouth to breathe, and causing the solution to flow into one
nostril, rinse round the septum and turbinates, and discharge from the
other nostril.

[0112] As mentioned previously, the present invention provides
pharmaceutical compositions for intranasal administration of
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol and related compounds, which may be delivered to the systemic
circulation via delivery across the nasal mucosa.

[0113] In one embodiment, the composition is further comprising an
absorption agent. In one embodiment, the composition is further
comprising one or more adhesive, binder, lubricant, glidant, disintegrant
or mixture thereof.

[0114] The compound of the invention as a pharmaceutical composition for
intranasal administration may be administered in any suitable way in the
nasal cavity, and the compound may be presented in any suitable dosage
form for such administration, e.g. in form of simple solutions or
dispersions, simple tablets, matrix tablets, capsules, powders, syrups,
dissolvable films, patches, lipophilic gels. In one embodiment, the
compound of the invention is administered in the form of a solid
pharmaceutical entity, suitably as a tablet or a capsule. In another
particular embodiment, the compound of the invention is administered in
the form of a dissolvable film.

[0115] In the case of intranasal administration of the compound of the
invention, conventional dosage forms may not be able to assure
therapeutic drug levels in because of physiological removal mechanism of
the oral cavity (washing effect of saliva and mechanical stress), which
remove the drug formulation away from the nasal mucosa, resulting in too
short exposure time and unpredictable absorption. To obtain the desired
therapeutic action it may therefore be necessary to prolong and improve
the contact between the compound of the invention and the nasal mucosa.
To fulfill the therapeutic requirement, formulations designed for
intranasal administration may therefore contain mucoadhesive agents to
maintain an intimate and prolonged contact of the formulation with the
absorption site; penetration enhancers, to improve drug permeation across
the mucosa; and enzyme inhibitors to eventually protect the drug from
degradation by means of nasal mucosal enzymes.

[0116] In a specific embodiment of the invention there is provided a
pharmaceutical composition comprising a therapeutically effective amount
of compound of the invention or a pharmaceutically acceptable acid
addition salt thereof for administration via the nasal mucosa.

[0117] In a further aspect the invention provides the use of said
composition for the preparation of a medicament for the treatment of
neurodegenerative disorders such as Parkinson's disease and Huntington's
disease.

[0118] In a further aspect the invention provides the use of the
pharmaceutical composition for the preparation of a medicament for the
treatment of psychoses, impotence, renal failure, heart failure or
hypertension.

[0119] In another aspect the invention provides the use of the
pharmaceutical composition for the manufacture of a medicament for the
treatment of cognitive impairment in a mammal.

[0120] In a still further aspect the invention provides the use of the
pharmaceutical composition for the manufacture of a medicament for the
treatment of restless legs syndrome (RLS) or periodic limb movement
disorder (PLMD).

[0121] In a still further aspect the invention provides the use of the
pharmaceutical composition for the manufacture of a medicament for the
treatment of erectile dysfunction.

[0122] In a different aspect the invention provides the use of the
pharmaceutical composition for the manufacture of a medicament for the
treatment of movement disorders, poverty of movement, dyskinetic
disorders, gait disorders or intention tremor in a mammal.

[0123] In a further aspect the invention provides the use of the
pharmaceutical composition for the treatment of neurodegenerative
disorders such as Parkinson's disease and Huntington's disease.

[0124] In a further aspect the invention provides the use of the
pharmaceutical composition for the treatment of psychoses, impotence,
renal failure, heart failure or hypertension.

[0125] In another aspect the invention provides the use of the
pharmaceutical composition for the treatment of cognitive impairment in a
mammal.

[0126] In a still further aspect the invention provides the use of the
pharmaceutical composition for the treatment of restless legs syndrome
(RLS) or periodic limb movement disorder (PLMD).

[0127] In a different aspect the invention provides the use of the
pharmaceutical composition for the treatment of movement disorders,
poverty of movement, dyskinetic disorders, gait disorders or intention
tremor in a mammal.

[0128] In separate aspects the invention provides the use of the
pharmaceutical composition for the manufacture of medicaments, which are
intended for administration via the oral mucosa.

[0129] The invention also provides a method of treating a mammal suffering
from a neurodegenerative disorder such as Parkinson's disease and
Huntington's disease comprising administering to the mammal a
therapeutically effective amount of the pharmaceutical composition.

[0130] In another aspect the invention also provides a method of treating
a mammal suffering from psychoses, impotence, renal failure, heart
failure or hypertension, comprising administering to the mammal a
therapeutically effective amount of the pharmaceutical composition.

[0131] In a further aspect the invention provides a method of treating a
mammal suffering from a cognitive impairment, comprising administering to
the mammal an effective amount of the pharmaceutical composition.

[0132] The invention also relates to a method of treating a mammal
suffering from restless legs syndrome (RLS) or periodic limb movement
disorder (PLMD), comprising administering to the mammal a therapeutically
effective amount of compound of the invention, or a pharmaceutically
acceptable addition salt thereof.

[0133] The invention also relates in a separate aspect to a method of
treating a mammal suffering from movement disorders, poverty of movement,
dyskinetic disorders, gait disorders or intention tremor comprising
administering to the mammal of the pharmaceutical composition.

[0134] The therapeutically effective amount of the compound of the
invention, calculated as the daily dose of the compound of the invention
above as the free base, is suitably between 0.001 and 12.5 mg/day, more
suitable between 0.005 and 10.0 mg/day, e.g. preferably between 0.01 and
5.0 mg/day. In a specific embodiment the daily dose of the compound of
the invention is between 0.1 and 1.0 mg/day.

[0135] In another embodiment the daily dose of the compound of the
invention is less than about 0.1 mg/day. In a separate embodiment the
daily dose of the compound of the invention is about 0.01 mg/day. In a
further embodiment the invention provides a formulation comprising from
0.0001 mg to 12.5 mg of the compound of the invention for delivery via
the nasal mucosa. In a further embodiment the invention provides a
formulation comprising from 0.0001 mg to 0.01 mg of the compound of the
invention for delivery via the nasal mucosa. In a further embodiment the
invention provides a formulation comprising from 0.001 mg to 0.10 mg of
the compound of the invention for delivery via the nasal mucosa. In a
further embodiment the invention provides a formulation comprising from
0.01 mg to 1.0 mg of the compound of the invention for delivery via the
nasal mucosa.

C. Transdermal Administration By "transdermal delivery", applicants
intend to include both transdermal and percutaneous administration, i.e.,
delivery by passage of an active ingredient through the skin and into the
bloodstream.

[0136] "Carriers" or "vehicles" as used herein refer to carrier materials
suitable for transdermal drug administration, and include any such
materials known in the art, e.g., any liquid, gel, solvent, liquid
diluent, solubilizer, or the like, which is non toxic and which does not
interact with other components of the composition in a deleterious
manner. Examples of suitable vehicles for use herein include water,
alcohols such as isopropyl alcohol and isobutyl alcohol, polyalcohols
such as glycerol, and glycols such as propylene glycol, and esters of
such polyols, (e.g., mono-, di-, or tri-glycerides).

[0137] "Penetration enhancement" or "permeation enhancement" as used
herein relates to an increase in the permeability of skin to a
pharmacologically active agent, namely, so as to increase the rate at
which the active ingredient permeates through the skin (i.e., flux) and
enters the bloodstream or the local site of action. The enhanced
permeation effected by using these enhancers can be observed by measuring
the rate of diffusion (or flux) of active ingredient through animal or
human skin or a suitable polymeric membrane using a diffusion cell
apparatus as described in the examples herein.

[0142] Other components may include diluents such as cellulose,
microcrystalline cellulose, hydroxypropyl cellulose, starch,
hydroxypropylmethyl cellulose and the like. Excipients can be added to
adjust the tonicity of the composition, such as sodium chloride, glucose,
dextrose, mannitol, sorbitol, lactose and the like. Acidic or basic
buffers can also be added to control the pH. Co-solvents or solubilizers
such as glycerol, polyethylene glycols, polyethylene glycols derivatives,
polyethylene glycol 660 hydroxystearate (Solutol HS15 from BASF),
butylene glycol, hexylene glycol, and the like, can also be added.

Transdermal Compositions

[0143] The compositions for transdermal administration include a compound
of the invention including fatty acid salts, and optionally can also
include other ingredients including, but not limited to, carriers and
excipients, such as permeation enhancers which promote transdermal
absorption of the active ingredient after transdermal administration.

[0144] The amount of active ingredient absorbed depends on many factors.
These factors include the active ingredient concentration, the active
ingredient delivery vehicle, the skin contact time, the area of the skin
dosed, the ratio of the ionized and unionized forms of the active
ingredient at the pH of the absorption site, the molecular size of the
active ingredient molecule, and the active ingredient's relative lipid
solubility.

Transdermal Devices

[0145] The transdermal device for delivering the active ingredients
described herein can be of any type known in the art, including the
monolithic, matrix, membrane, and other types typically useful for
administering active ingredients by the transdermal route. Such devices
are disclosed in U.S. Pat. Nos. 3,996,934; 3,797,494; 3,742,951;
3,598,122; 3,598,123; 3,731,683; 3,734,097; 4,336,243; 4,379,454;
4,460,372; 4,486,193; 4,666,441; 4,615,699; 4,681,584; and 4,558,580
among others.

[0146] These devices tend to be flexible, adhere well to the skin, and
have a polymeric backing (covering) that is impermeable to the active
ingredient to be delivered, so that the active ingredient is administered
uni-directionally through the skin. The active ingredient, or
pharmaceutically acceptable salt thereof, is typically present in a
solution or dispersion, which can be in the form of a gel, a solution, or
a semi-solid, and which aids in active ingredient delivery through the
stratum corneum of the epidermis and to the dermis for absorption.

Membrane Devices

[0147] Membrane devices typically have four layers: (1) an impermeable
backing, (2) a reservoir layer, (3) a membrane layer (which can be a
dense polymer membrane or a microporous membrane), and (4) a contact
adhesive layer which either covers the entire device surface in a
continuous or discontinuous coating or surrounds the membrane layer.
Examples of materials that may be used to act as an impermeable layer are
high, medium, and low density polyethylene, polypropylene,
polyvinylchloride, polyvinylidene chloride, polycarbonate, polyethylene
terepthalate, and polymers laminated or coated with aluminum foil. Others
are disclosed in the standard transdermal device patents mentioned
herein. In certain embodiments in which the reservoir layer is fluid or
is a polymer, the outer edge of the backing layer can overlay the edge of
the reservoir layer and be sealed by adhesion or fusion to the diffusion
membrane layer. In such instances, the reservoir layer need not have
exposed surfaces.

[0148] The reservoir layer is underneath the impermeable backing and
contains a carrier liquid, typically water and/or an alcohol, or polyol
or ester thereof, and may or may not contain the active ingredients. The
reservoir layer can include diluents, stabilizers, vehicles, gelling
agents, and the like in addition to the carrier liquid and active
ingredients.

[0149] The diffusion membrane layer of the laminate device can be made of
a dense or microporous polymer film that has the requisite permeability
to the active ingredient and the carrier liquid. Preferably, the membrane
is impermeable to ingredients other than the active ingredient and the
carrier liquid, although when buffering at the skin surface is desired,
the membrane should be permeable to the buffer in the composition as
well. Examples of polymer film that may be used to make the membrane
layer are disclosed in U.S. Pat. Nos. 3,797,454 and 4,031,894. The
preferred materials are polyurethane, ethylene vinyl alcohol polymers,
and ethylene/vinyl acetate.

Monolithic Matrices

[0150] The second class of transdermal systems is represented by
monolithic matrices. Examples of such monolithic devices are U.S. Pat.
Nos. 4,291,014; 4,297,995; 4,390,520 and 4,340,043. Others are known to
those of ordinary skill in this art.

[0151] Monolithic and matrix type barrier transdermal devices typically
include: (1) Porous polymers or open-cell foam polymers, such as
polyvinyl chloride (PVC), polyurethanes, polypropylenes, and the like;
(2) Highly swollen or plasticized polymers such as cellulose, HEMA or
MEMA or their copolymers, hydroxypropyl methylcellulose (HPMC),
hydroxyethyl methylcellulose (HEMC), and the like, polyvinyl alcohol
(PVA)/polyvinylpyrollidone (PVP), or other hydrogels, or PVC,
polyurethane, ethylene/vinyl acetate, or their copolymers; (3) Gels of
liquids, typically including water and/or hydroxyl-containing solvents
such as ethanol, and often containing gelling agents such PVP,
carboxymethylcellulose (CMC), hydroxypropylcellulose such as sold under
the tradename Klucel®, HPMC, alginates, kaolinate, bentonite, or
montmorillonite, other clay fillers, stearates, silicon dioxide
particles, and the like; (4) Nonwoven materials made of textiles,
celluloses, polyurethanes, polyester, or other fiber; (5) Sponges, which
can be formed from natural or foamed polymers; and (6) Adhesives, ideally
dermatologically-acceptable pressure sensitive adhesives, for example,
silicone adhesives or acrylic adhesives.

Polymeric Barrier Materials

[0152] Representative polymeric barrier materials include, but are not
limited to: Polycarbonates, such as those formed by phosgenation of a
dihydroxy aromatic such as bisphenol A, including materials are sold
under the trade designation Lexan® (the General Electric Company);
Polyvinylchlorides, such as Geon® 121 (B. G. Goodrich Chemical
Company); Polyamides ("nylons"), such as polyhexamethylene adipamide,
including NOMEX® (E. I. DuPont de Nemours & Co.).

[0154] Other polymers such as polyurethanes, polyimides,
polybenzimidazoles, polyvinyl acetate, aromatic and aliphatic,
polyethers, cellulose esters, e.g., cellulose triacetate; cellulose;
colledion (cellulose nitrate with 11% nitrogen); epoxy resins; olefins,
e.g., polyethylene, polypropylene; polyvinylidene chloride; porous
rubber; cross linked poly(ethylene oxide); cross-linked
polyvinylpyrrolidone; cross-linked polyvinyl alcohol); polyelectrolyte
structures formed of two ionically associated polymers of the type as set
forth in U.S. Pat. Nos. 3,549,016 and 3,546,141; derivatives of
polystyrene such as poly(sodium styrenesulfonate) and
poly(vinylbenzyltrimethyl-ammonium chloride);
poly(hydroxyethylmethacrylate); poly(isobutylvinyl ether), and the like,
may also be used. A large number of copolymers which can be formed by
reacting various proportions of monomers from the above list of polymers
are also useful. If the membrane or other barrier does not have a
sufficiently high flux, the thickness of the membrane or barrier can be
reduced. However, the thickness should not be reduced to the point where
it is likely to tear, or to a point where the amount of active ingredient
which can be administered is too low.

Adhesives

[0155] The transdermal drug delivery compositions typically include a
contact adhesive layer to adhere the device to the skin. The active agent
may, in some embodiments, reside in the adhesive. Adhesives include
polyurethanes; acrylic or methacrylic resins such as polymers of esters
of acrylic or methacrylic acid with alcohols such as n-butanol,
n-pentanol, isopentanol, 2-methylbutanol, 1-methylbutanol,
1-methylpentanol, 2-methylpentanol, 3-methylpentanol, 2-ethylbutanol,
isooctanol, n-decanol, or n-dodecanol, alone or copolymerized with
ethylenically unsaturated monomers such as acrylic acid, methacrylic
acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamides,
N-alkoxymethyl methacrylamides, N-tertbutylacrylamide, itaconic acid,
vinylacetate, N-branched alkyl maleamic acids wherein the alkyl group has
10 to 24 carbon atoms, glycol diacrylates, or mixtures of these; natural
or synthetic rubbers such as styrenebutadiene, butylether, neoprene,
polyisobutylene, polybutadiene, and polyisoprene; polyvinylacetate;
unreaformaldehyde resins; phenolformaldehyde resins; resorcinol
formaldehyde resins, cellulose derivatives such as ethylcellulose,
methylcellulose, nitrocellulose, cellulose acetatebutyrate, and
carboxymethyl cellulose; and natural gums such as guar, acacia, pectins,
starch, dextrin, albumin, gelatin, casein, etc. The adhesives can be
compounded with tackifiers and stabilizers, as is well known in the art.

[0156] Representative silicone adhesives include silicone elastomers based
on monomers of silanes, halosilanes, or CMS alkoxysilanes, especially
polydimethylsiloxanes which may be used alone or formulated with a
silicone tackifier or silicone plasticizer which are selected from
medically acceptable silicone fluids, i.e. non-elastomeric silicones
based on silanes, halosilanes or C1-18 alkoxysilanes. Typical
silicone adhesives are available from Dow Corning under the tradename
SILASTIC®.

Liquid Vehicles

[0157] Transdermal compositions can include a variety of components,
including a liquid vehicle, typically a C2-4 alkanol such as
ethanol, isopropanol, n-propanol, butanol, a polyalcohol or glycol such
as propylene glycol, butylene glycol, hexylene glycol, ethylene glycol,
and/or purified water. The vehicle is typically present in an amount of
between about 5 and about 75% w/w, more typically, between about 15.0%
and about 65.0% w/w, and, preferably, between about 20.0 and 55.0% w/w.

[0158] Water augments the solubility of hydrophilic active agents in the
composition, and accelerates the release of lipophilic active agents from
a composition. Alcohols, such as ethanol, increase the stratum corneum
liquid fluidity or function to extract lipids from the stratum corneum.
As discussed herein, the glycols can also act as permeation enhancers.

Controlled Release of the Active Agent

[0159] The administration of the active agent can be controlled by using
controlled release compositions, which can provide rapid or sustained
release, or both, depending on the compositions. There are numerous
particulate drug delivery vehicles known to those of skill in the art
which can include the active ingredients, and deliver them in a
controlled manner. Examples include particulate polymeric drug delivery
vehicles, for example, biodegradable polymers, and particles formed of
non-polymeric components. These particulate drug delivery vehicles can be
in the form of powders, microparticles, nanoparticles, microcapsules,
liposomes, and the like. Typically, if the active agent is in particulate
form without added components, its release rate depends on the release of
the active agent itself. In contrast, if the active agent is in
particulate form as a blend of the active agent and a polymer, the
release of the active agent is controlled, at least in part, by the
removal of the polymer, typically by dissolution or biodegradation.

[0160] In one embodiment, the transdermal compositions can provide an
initial rapid release of the active ingredient followed by a sustained
release of the active ingredient. U.S. Pat. No. 5,629,011 provides
examples of this type of composition. There are numerous transdermal
compositions that use transdermal delivery to deliver nicotine in a
time-release manner (such as rate-controlling membranes), including
currently marketed nicotine replacement therapies. These are also
suitable for administering the compounds described herein.

Semi-Solid Dosage Forms

[0161] In one embodiment, the transdermal dosage form is not a "patch,"
but rather, a semisolid dosage form such as a gel, cream, ointment,
liquid, etc. In this embodiment, one can augment patient's compliance and
cover a broader surface area than can be covered with a patch.

[0162] In this embodiment, particularly when used for pain treatment, the
dosage form can include other active and inactive components typically
seen in semisolid dosage forms used to treat pain. These include, but are
not limited to, menthol, wintergreen, capsaicin, aspirin, NSAIDs,
narcotic agents (e.g. fentanyl), alcohols, oils such as emulsion oil, and
solvents such as DMSO.

Iontophoresis

[0163] In addition to delivery via transdermal drug delivery devices and
semi-solid dosage forms, the active ingredients can also be delivered via
iontophoresis. Iontophoresis is a non-invasive method of propelling high
concentrations of a charged substance, such as the active ingredients
described herein, transdermal by repulsive electromotive force. The
technique involves using a small electrical charge applied to an
iontophoretic chamber containing a similarly charged active agent and its
vehicle. The skin's permeability is altered upon application of the
charge, and this increases migration of the active ingredient into the
epidermis.

[0164] Iontophoresis can be used to transdermally deliver the active
agents, using active transportation within an electric field, typically
by electromigration and electroosmosis. These movements are typically
measured in units of chemical flux, commonly μmol/cm2*h. The
isoelectric point of the skin is approximately 4. Under physiological
conditions, where the surface of the skin is buffered at or near 7.4, the
membrane has a net negative charge, and electroosmotic flow is from anode
(-) to cathode (+). Electroosmosis augments the anodic delivery of the
(positively charged) active agents described herein.

[0165] Iontophoresis devices include two electrodes, which are typically
attached to a patient, each connected via a wire to a microprocessor
controlled electrical instrument. The active agents are placed under one
or both of the electrodes, and are delivered into the body as the
instrument is activated.

[0166] Typically, ions are delivered into the body from an aqueous drug
reservoir contained in the iontophoretic device, and counter ions of
opposite charge are delivered from a "counter reservoir." Solutions
containing the active ingredient, and also solutions of the counter ions,
can be stored remotely and introduced to an absorbent layer of the
iontophoresis electrode at the time of use. Examples of such systems are
described in U.S. Pat. Nos. 5,087,241; 5,087,242; 5,846,217; and
6,421,561, the contents of which are hereby incorporated by reference.
Alternatively, as described in U.S. Pat. No. 5,685,837, the active agents
can be pre-packaged in dry form into the electrode(s). This approach
requires a moisture activation step at the time of use.

[0167] Solutions of the active agents can be co-packaged with the
iontophoretic device, ideally positioned apart from the electrodes and
other metallic components until the time of use. This technique, and
suitable devices, are described, for example, in U.S. Pat. Nos.
5,158,537; 5,288,289; 5,310,404; 5,320,598; 5,385,543; 5,645,527;
5,730,716; and 6,223,075. In these devices, a co-packaged electrolyte
constituent liquid is stored remotely from the electrodes, in a
rupturable container and a mechanical action step at the time of use
induces a fluid transfer to a receiving reservoir adjacent to the
electrodes. These systems enable precise fluid volumes to be incorporated
at the time of manufacture to avoid overfilling.

[0168] In addition to solutions, the active agents can be present in a
pre-formed gel, as described in U.S. Pat. No. 4,383,529, incorporated by
reference. Thus, a preformed gel containing the active agent can be
transferred into an electrode receptacle at the time of use. This system
can be advantageous in that it provides a precise pre-determined volume
of the gel, thus preventing over-filling. Further, since the active agent
is present in a gel composition, it is less likely to leak during storage
or transfer.

[0169] In some embodiments, the transdermal drug delivery is carried out
using devices that include a polymeric barrier, adhered to the skin with
a suitable adhesive, and which also include a suitable amount of the
active ingredients, or salts thereof, in solution or dispersion and in
contact with the skin or a rate-controlling membrane may be used between
the active-containing composition and the skin. In others, the delivery
is carried out using semisolid compositions, such as cremes or lotions,
which include the active ingredients, and which are applied to the skin.
In still other embodiments, the active ingredients are delivered using
iontophoresis, wherein the positively charged active agents are
administered by electroosmosis. There may also be embodiments wherein the
active ingredient(s) is formulated within the matrix of the adhesive.

[0170] As previously indicated, the present invention provide transdermal
compositions of
(4aR,10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-
-diol and related compounds, which may be delivered to the systemic
circulation via delivery across the skin.

[0171] In one embodiment, the composition is further characterized as
patch. In one embodiment, the composition is further characterized as a
semisolid dosage form. In one embodiment, the composition is further
characterized as a gel, lotion or creme. In one embodiment, the
composition is further characterized as a controlled release formulation.
In one embodiment, the composition is further comprising a permeation
enhancer. In one embodiment, the composition is further comprising one or
more adhesive, binder, lubricant, glidant, disintegrant or mixture
thereof.

[0172] The compound of the invention as a pharmaceutical composition for
transdermal administration may be administered in any suitable way across
the skin, and the compound may be presented in any suitable dosage form
for such administration, e.g. in form of simple solutions or dispersions,
simple tablets, matrix tablets, capsules, powders, syrups, dissolvable
films, patches, lipophilic gels. In another embodiment, the compound of
the invention is administered in the form of a dissolvable film.

[0173] In a specific embodiment of the invention, there is provided a
transdermal composition comprising a therapeutically effective amount of
the compound of the invention, or a pharmaceutically acceptable acid
addition salt thereof, for administration across the skin.

[0174] In a further aspect the invention provides the use of said
composition for the preparation of a medicament for the treatment of
neurodegenerative disorders such as Parkinson's disease and Huntington's
disease.

[0175] In a further aspect the invention provides the use of the
transdermal composition for the preparation of a medicament for the
treatment of psychoses, impotence, renal failure, heart failure or
hypertension.

[0176] In another aspect the invention provides the use of the transdermal
composition for the manufacture of a medicament for the treatment of
cognitive impairment in a mammal.

[0177] In a still further aspect the invention provides the use of the
transdermal composition for the manufacture of a medicament for the
treatment of restless legs syndrome (RLS) or periodic limb movement
disorder (PLMD).

[0178] In a still further aspect the invention provides the use of the
transdermal composition for the manufacture of a medicament for the
treatment of erectile dysfunction.

[0179] In a different aspect the invention provides the use of the
transdermal composition for the manufacture of a medicament for the
treatment of movement disorders, poverty of movement, dyskinetic
disorders, gait disorders or intention tremor in a mammal.

[0180] In a further aspect the invention provides the use of the
transdermal composition for the treatment of neurodegenerative disorders
such as Parkinson's disease and Huntington's disease.

[0181] In a further aspect the invention provides the use of the
transdermal composition for the treatment of psychoses, impotence, renal
failure, heart failure or hypertension.

[0182] In another aspect the invention provides the use of the transdermal
composition for the treatment of cognitive impairment in a mammal.

[0183] In a still further aspect the invention provides the use of the
transdermal composition for the treatment of restless legs syndrome (RLS)
or periodic limb movement disorder (PLMD).

[0184] In a different aspect the invention provides the use of the
transdermal composition for the treatment of movement disorders, poverty
of movement, dyskinetic disorders, gait disorders or intention tremor in
a mammal.

[0185] In separate aspects the invention provides the use of the
transdermal composition for the manufacture of medicaments, which are
intended for administration via the skin.

[0186] The invention also provides a method of treating a mammal suffering
from a neurodegenerative disorder such as Parkinson's disease and
Huntington's disease comprising administering to the mammal a
therapeutically effective amount of the transdermal composition.

[0187] In another aspect the invention also provides a method of treating
a mammal suffering from psychoses, impotence, renal failure, heart
failure or hypertension, comprising administering to the mammal a
therapeutically effective amount of the transdermal composition.

[0188] In a further aspect the invention provides a method of treating a
mammal suffering from a cognitive impairment, comprising administering to
the mammal an effective amount of the transdermal composition.

[0189] The invention also relates to a method of treating a mammal
suffering from restless legs syndrome (RLS) or periodic limb movement
disorder (PLMD), comprising administering to the mammal a transdermal
composition of the compound of the invention, or a pharmaceutically
acceptable addition salt thereof.

[0190] The invention also relates in a separate aspect to a method of
treating a mammal suffering from movement disorders, poverty of movement,
dyskinetic disorders, gait disorders or intention tremor comprising
administering to the mammal of the pharmaceutical composition.

[0191] The therapeutically effective amount of the compound of the
invention, calculated as the daily dose of the compound of the invention
above as the free base, is suitably between 0.001 and 12.5 mg/day, more
suitable between 0.005 and 10.0 mg/day, e.g. preferably between 0.01 and
5.0 mg/day. In a specific embodiment the daily dose of the compound of
the invention is between 0.1 and 1.0 mg/day.

[0192] In another embodiment the daily dose of the compound of the
invention is less than about 0.1 mg/day. In a separate embodiment the
daily dose of the compound of the invention is about 0.01 mg/day. In a
further embodiment the invention provides a formulation comprising from
0.0001 mg to 12.5 mg of the compound of the invention for transdermal
delivery. In a further embodiment the invention provides a formulation
comprising from 0.0001 mg to 0.01 mg of the compound of the invention for
transdermal delivery. In a further embodiment the invention provides a
formulation comprising from 0.001 mg to 0.10 mg of the compound of the
invention for transdermal delivery. In a further embodiment the invention
provides a formulation comprising from 0.01 mg to 1.0 mg of the compound
of the invention for transdermal delivery.

[0193] Ultimately, the exact dose of the compound of the invention and the
particular formulation to be administered depend on a number of factors,
e.g., the condition to be treated, the desired duration of the treatment
and the rate of release of the active agent. For example, the amount of
the active agent required and the release rate thereof may be determined
on the basis of known in vitro or in vivo techniques, determining how
long a particular active agent concentration in the blood plasma remains
at an acceptable level for a therapeutic effect.

[0200] Analytical LC/MS data were obtained on a PE Sciex API 150EX
instrument equipped with atmospheric pressure photo ionization and a
Shimadzu LC-8A/SLC-10A LC system. Purity was determined by integration of
the UV (254 nm) and ELSD traces. MS instruments are from Peskier (API),
equipped with APPI-source and operated in positive ion mode. The
retention times in the UV-trace (RT) are expressed in min. Solvents A was
made of 0.05% TFA in water, while solvent B was made of 0.035% TFA and 5%
water in acetonitrile. Several different methods have been used:

[0203] X-ray crystal structure determination was performed as follows. The
crystal of the compound was cooled to 120 K using a Cryostream nitrogen
gas cooler system. The data were collected on a Siemens SMART Platform
diffractometer with a CCD area sensitive detector. The structures were
solved by direct methods and refined by full-matrix least-squares against
F2 of all data. The hydrogen atoms in the structures could be found
in the electron density difference maps. The non-hydrogen atoms were
refined anisotropically. All the hydrogen atoms were at calculated
positions using a riding model with O--H=0.84, C--H=0.99-1.00,
N--H=0.92-0.93 Å. For all hydrogen atoms the thermal parameters were
fixed [U(H)=1.2 U for attached atom]. The Flack x-parameters are in the
range 0.0(1)-0.05(1), indicating that the absolute structures are
correct. Programs used for data collection, data reduction and absorption
were SMART, SAINT and SADABS [cf. "SMART and SAINT, Area Detector Control
and Integration Software", Version 5.054, Bruker Analytical X-Ray
Instruments Inc., Madison, USA (1998), Sheldrick "SADABS, Program for
Empirical Correction of Area Detector Data" Version 2.03, University of
Gottingen, Germany (2001)]. The program SHELXTL [cf. Sheldrick "SHELXTL,
Structure Determination Programs", Version 6.12, Bruker Analytical X-Ray
Instruments Inc., Madison, USA (2001)] was used to solve the structures
and for molecular graphics.

Synthesis of the Compounds of the Invention

[0204] Starting from compound 1 whose synthesis is described in the
literature prepared as described in Taber et al., J. Am. Chem. Soc., 124
(42), 12416 (2002), compound 8 can be prepared as described herein in
eight steps. This material can be resolved by chiral SFC as described
herein to give compounds 9 and ent-9. After cleavage of the
Boc-protective group, reductive amination can be used to introduce the
n-propyl group on the nitrogen atom. The resulting masked catechol amines
can be deprotected under standard conditions by treatment with 48% HBr or
by reaction with BBr3 to give compounds 10 and ent-10.

[0205] The enantiomer of example 1 (compound 10) and ent-example 1
(ent-compound 10), can be prepared in a similar manner from ent-9. The
racemate of example 1, rac-example 1, can be prepared by mixing a 1:1
mixture of example 1 and ent-example 1. It can also be obtained from
non-resolved compound 8 or a 1:1 mixture of compound 9/ent-9 as described
above for the pure enantiomers. Alternatively, rac-example 1 can be
prepared as described in the literature (Cannon et al., J. Heterocycl.
Chem. 17, 1633 (1980)).

##STR00005##

Synthesis of compounds 9 and ent-9.

7-Iodo-1,2,6-trimethoxy-naphthalene (compound 2)

##STR00006##

[0207] To a stirred solution of compound 1 (26.2 g; prepared as described
in Taber et al., J. Am. Chem. Soc., 124 (42), 12416 (2002)) in dry THF
(200 mL) under argon and at -78° C. was slowly added s-butyl
lithium (1.2 M in cyclohexane, 110 mL). The solution was stirred at
-78° C. for 3 h. A solution of iodine (30.5 g) in dry THF (50 mL)
was added over a period of 10 min. The resulting mixture was then stirred
for another 10 min at -78° C. The reaction mixture was quenched by
the addition of sat. NH4Cl (100 mL), water (240 mL), and Et2O
(240 mL). The organic layer was washed with 10% aqueous sodium sulfite
solution (100 mL), dried (Na2SO4) and concentrated in vacuo.
The crude material was purified by distilling off unreacted starting
material. The residue was further purified by silica gel chromatography
(EtOAc/heptane) to produce an impure solid material, which was purified
by precipitation from EtOAc/heptane affording 11.46 g of compound 2.

(E/Z)-3-(3,7,8-Trimethoxy-naphthalen-2-yl)-acrylonitrile (compound 3)

##STR00007##

[0209] To a suspension of compound 2 (3.41 g) in dry acetonitrile (10.7
mL) in a microwave reactor vial was added acrylonitrile (1.19 mL)
Pd(OAc)2 (73 mg), and triethylamine (1.48 mL). The vial was sealed,
and the mixture was heated for 40 min at 145° C. under microwave
irradiation. This procedure was carried out two more times (using a total
of 10.23 g of compound 5). The crude reaction mixtures were combined and
the catalyst was filtered off, and the filtrate was concentrated in
vacuo. The residue was partitioned between Et2O (300 mL) and 2M HCl
(150 mL). The organic layer was washed with brine (100 mL), dried
(Na2SO4) and concentrated in vacuo. The crude material (7.34 g)
was purified by silica gel chromatography (EtOAc/heptane) to produce 5.23
g of compound 3 as a mixture of olefin isomers.

3-(3,7,8-Trimethoxy-naphthalen-2-yl)-propionitrile (compound 4)

##STR00008##

[0211] Compound 3 (5.23 g) was dissolved in CHCl3 (15 mL) and 99%
EtOH (100 mL). 10% Pd/C (0.8 g) was added and the solution was
hydrogenated for 45 min under a hydrogen pressure of 3 bar using a Parr
shaker. The catalyst was filtered off, and the filtrate was passed
through a small plough of silica gel (eluent: 99% EtOH). Yield: 4.91 g
compound 4 as a white solid.

[0213] Compound 4 (5.0 g) was dissolved in 99% EtOH (150 mL) and the
mixture was heated to reflux under nitrogen atmosphere. Sodium metal (5
g) was added in small lumps over 3 h. The mixture was refluxed for an
additional 2 h, before it was stirred at rt for 2 days. Then it was
heated to reflux again, and more sodium metal (3.68 g) was added and the
mixture was refluxed overnight. After cooling on an ice/water bath, the
reaction was quenched by the addition of solid ammonium chloride (20 g)
and water (25 mL). The resulting mixture was filtered, and the filtrate
was concentrated in vacuo. The residue was partitioned between diethyl
ether (50 mL) and water (50 mL). The aqueous layer was neutralized with
37% HCl and extracted with diethyl ether (2×50 mL). The combined
organic extracts were washed with brine (50 mL), dried (MgSO4) and
concentrated in vacuo to afford an oil. This material was dissolved in
THF (50 mL) and treated with Boc2O (2.34 g) and Et3N (1.78 mL)
at rt. After six days the volatiles were removed in vacuo and the residue
was purified by silica gel chromatography (EtOAc/heptane). This provided
impure compound 5 (1.52 g).

[0215] Compound 5 (1.52 g from the previous step) was dissolved in MeOH
(20 mL). 37% HCl (3.5 mL) was added, and the mixture was refluxed for 4
h. The volatiles were removed in vacuo, using toluene to azeotropically
remove the water. This provided impure compound 6 (0.89 g) as an yellow
oil.

[0217] Compound 6 (0.89 g) was dissolved in MeOH (10 mL) and NaCNBH3
(0.19 g) was added. The reaction was stirred overnight at rt. The crude
mixture was cooled on an ice/water bath, before it was quenched with 2 M
HCl in Et2O (1 mL). The mixture was partitioned between Et2O
(50 mL), water (50 mL), and 2 M NaOH (10 mL). The aqueous layer was
extracted with diethyl ether (3×50 mL). The combined organic layers
were dried (MgSO4) and concentrated in vacuo to afford the impure
free amine (compound 7). This material was dissolved in THF (25 mL) and
treated with Boc2O (0.68 g) and Et3N (0.86 mL) at rt for 1 h.
The crude mixture was concentrated in vacuo, and the residue was purified
by silica gel chromatography (EtOAc/heptane) to provide 1.18 g of racemic
compound 8 sufficiently pure for the next step.

[0221] Compound ent-9 (0.52 g) was dissolved in MeOH (15 mL) and treated
with 5 M HCl in Et2O (7.5 mL) at rt for 2 h. The mixture was
concentrated in vacuo and the solid was dried in vacuo to give compound
ent-9' as a white solid. LC/MS (method 14): RT 1.31 min.

[0223] Compound 9 (0.5 g) was dissolved in 99% EtOH (5 mL) and treated
with 2M HCl in Et2O (4 mL) overnight at rt. The crude mixture was
concentrated in vacuo, and the residue was partitioned between EtOAc and
10% aqueous NaOH (5 mL). The aqueous layer was extracted with EtOAc, and
the combined organic layers were washed with brine, dried (MgSO4),
concentrated in vacuo. The residue was dissolved in 99% EtOH (5 mL) and
treated with propionic aldehyde (0.52 mL), NaCNBH3 (0.45 g), and
AcOH (3 drops) overnight at rt. The crude mixture was portioned between
sat. aqueous NaHCO3 (12.5 mL), water (12.5 mL), and EtOAc
(2×25 mL). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated in vacuo. The residue was purified
by silica gel chromatography (MeOH/EtOAc). The obtained intermediate was
treated with 48% HBr (3 mL) at 150° C. for 1 h under microwave
conditions, before the crude mixture was stored at 4° C.
overnight. The precipitated material was isolated by filtration and dried
in vacuo. Yield of compound 10: 103 mg as a solid. LC/MS (method 25): RT
0.77 min.

[0225] The procedure described for compound 10 was followed starting from
compound ent-9' (0.5 g; the HCl salt was liberated by partitioning
between EtOAc and 10% aqueous NaOH before the reductive amination step).
Yield of compound ent-10: 70 mg as a solid. LC/MS (method 25): RT 0.70
min. A small sample of compound ent-10 was dissolved in MeOH and allowed
to crystallize slowly at rt over 2 months. The formed white crystals were
collected and subjected to X-ray analysis (cf. FIG. 1). The absolute
configuration of compound ent-10 was determined by X-ray crystallography
and allowed for unambiguous determination of the stereochemistry of
compounds 9 and 10 and hence their related compounds.

Example 2

General Diester syntheses

[0226] The scheme below provides a general procedure for the conversion of
catecholamines to the symmetric, asymmetric and mono esters of compound
10.

##STR00016##

wherein each Rx, Ry, and Rz is independently C1-6
alkanoyl, cycloalkylalkyl, phenylacetyl or benzoyl, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.
Briefly, the catechol amine was treated with acylchloride using TFA as
solvent. The crude acyl catecholamine(s) was purified by aluminum oxide
chromatography (for a reference on this transformation, see for example:
Wikstrom, Dijkstra, Cremers, Andren, Marchais, Jurva; WO 02/14279). Each
of the symmetric, asymmetric and mono-esters described in this example
falls within the scope of this invention.

[0227] As a working example, but without limiting the scope of the subject
invention, a symmetrical diester was prepared in a similar manner as
described above starting from compound 10 (44 mg) and pivaloyl chloride.
Yield of Example 3 was 14 mg as a white solid. LC/MS (method 14): RT 2.45
min, ELSD 97.7%, UV 83.9%. MH.sup.+: 430.2.

Pharmacological Data

Example 4

Pharmacological Testing In Vitro I

[0228] D1 cAMP Assay

[0229] The ability of the compounds to either stimulate or inhibit the
D1 receptor mediated cAMP formation in CHO cells stably expressing
the human recombinant D1 receptor was measured as follows. Cells
were seeded in 96-well plates at a concentration of 11000 cells/well 3
days prior to the experiment. On the day of the experiment the cells were
washed once in preheated G buffer (1 mM MgCl2, 0.9 mM CaCl2, 1
mM IBMX (3-i-butyl-1-methylxanthine) in PBS (phosphate buffered saline))
and the assay was initiated by addition of 100 micro-L of a mixture of 30
nM A68930 and test compound diluted in G buffer (antagonism) or test
compound diluted in G buffer (agonism).

[0230] The cells were incubated for 20 minutes at 37° C. and the
reaction was stopped by the addition of 100 micro-L S buffer (0.1 M HCl
and 0.1 mM CaCl2) and the plates were placed at 4° C. for 1
h. 68 micro-L N buffer (0.15 M NaOH and 60 mM NaOAc) was added and the
plates were shaken for 10 minutes. 60 micro-1 of the reaction were
transferred to cAMP FlashPlates (DuPont NEN) containing 40 micro-L 60 mM
Sodium acetate pH 6.2 and 100 micro-L IC mix (50 mM Sodium acetate pH
6.2, 0.1% sodium azide, 12 mM CaCl2, 1% BSA (bovine serum albumin)
and 0.15 micro-Ci/mL 125I-cAMP) were added. Following an 18 h
incubation at 4° C. the plates were washed once and counted in a
Wallac TriLux counter. Compound 10 was demonstrated to act as a D1
agonist in this assay with an EC50 of 15.5 nM and an intrinsic
activity (efficacy) of 100%. In comparison, apomorphine and dopamine were
D1 agonists in this assay with EC50-values of 52 nM and 43 nM,
respectively and intrinsic activities (efficacies) of 86% and 100%,
respectively.

Example 5

Pharmacological Testing In Vitro II

[0231] D2 cAMP Assay

[0232] The ability of the compounds to either stimulate or inhibit the
D2 receptor mediated inhibition of cAMP formation in CHO cells
transfected with the human D2 receptor was measured as follows.
Cells were seeded in 96 well plates at a concentration of 8000 cells/well
3 days prior to the experiment. On the day of the experiment the cells
were washed once in preheated G buffer (1 mM MgCl2, 0.9 mM
CaCl2, 1 mM IBMX in PBS) and the assay was initiated by addition of
100 micro-1 of a mixture of 1 micro-M quinpirole, 10 microM forskolin and
test compound in G buffer (antagonism) or 10 micro-M forskolin and test
compound in G buffer (agonism).

[0233] The cells were incubated 20 minutes at 37° C. and the
reaction was stopped by the addition of 100 microL S buffer (0.1M HCl and
0.1 mM CaCl2) and the plates were placed at 4° C. for 1 h. 68
microL N buffer (0.15 M NaOH and 60 mM Sodium acetate) were added and the
plates were shaken for 10 minutes. 60 micro-L of the reaction were
transferred to cAMP FlashPlates (DuPont NEN) containing 40 micro-L 60 mM
NaOAc pH 6.2 and 100 micro-L IC mix (50 mM NaOAc pH 6.2, 0.1% Sodium
azide, 12 mM CaCl2, 1% BSA and 0.15 micro-Ci/ml 125I-cAMP) were
added. Following an 18 h incubation at 4° C. the plates were
washed once and counted in a Wallac TriLux counter. Compound 10 was
demonstrated to act as a D5 agonist in this assay with an EC50
of 0.11 nM and an intrinsic activity (efficacy) of 100%. In comparison,
apomorphine and dopamine were D2 agonists in this assay with
EC50-values of 3.9 nM and 21 nM, respectively and intrinsic
activities (efficacies) of 100% for both compounds.

Example 6

Pharmacological Testing In Vitro III

D5 Assay

[0234] Concentration-dependent stimulation of intracellular Ca2+
release by dopamine in hD5-transfected CHO-Ga16 cells. The cells
were loaded with fluoro-4, a calcium indicator dye, for 1 h. Calcium
response (fluorescence change) was monitored by FLIPR (fluorometric
imaging plate reader) for 2.5 min. Peak responses (EC50) were
averaged from duplicate wells for each data point and plotted with drug
concentrations (cf. FIG. 2 for dopamine). Compound 10 was demonstrated to
act as a D5 agonist in this assay with an EC50 of 0.06 nM and
an intrinsic activity (efficacy) of 95%. In comparison, apomorphine and
dopamine were D5 agonists in this assay with EC50-values of
0.36 nM and 1.6 nM, respectively and intrinsic activities (efficacies) of
88% and 100%, respectively.

Example 7

Pharmacological Testing In Vivo I

D1/D2 Dissections

[0235] Dopamine agonists can have activity at either the D1 receptors, the
D2 receptors, or both. We have used the rotation response in rats with
unilateral 6-OHDA lesions to assess compounds for their ability to
stimulate both receptor types and induce rotation [Ungerstedt and
Arbuthnott, Brain Res. 1970, 24, 485; Setler et al., Eur. J. Pharmacol.
1978, 50 (4), 419; and Ungerstedt et al. "Advances in Dopamine Research"
(Kohsaka, Ed.), Pergamon Press, Oxford, p. 219 (1982)]. 6-OHDA
(6-hydroxydopamine) is a neurotoxin used by neurobiologists to
selectively kill dopaminergic neurons at the site of injection in the
brain in experimental animals. In the 6-OHDA model the nigrostraital
dopamine cells are destroyed on one side of the brain (unilateral) by
injecting 6-OHDA into the median forebrain bundle, located in front of
the substantia nigra. The effects of the unilateral lesion combined with
the administration of dopamine agonists such as apomorphine will induce
rotation behaviour. Rats weighing 200-250 g were subjected to unilateral
6-OHDA lesions. Animals were permitted minimum three weeks to recover
before being tested for rotation response to amphetamine (2.5 mg/kg
subcutaneously) and only animals that responded by ipsolateral rotations
were used in subsequent dyskinesia studies (examples 8 and 9).
Amphetamine increases dopamine levels in the synapse by blocking reuptake
and increasing release from presynaptic terminals. This effect is greater
in the unlesioned side causing the animals to rotate in the opposite
direction as compared to their response to direct agonists such as L-DOPA
and apomorphine that act predominantly on the lesioned side of the brain.
For D1/D2 in vivo dissection studies were trained on apomorphine (0.1
mg/kg subcutaneously) before being using in experiments and only animals
that repeatedly rotated at least 350 times in 90 min were included. Rats
where then randomly allocated to the three treatment groups balancing the
groups for the animals' rotation response to apomorphine (0.1 mg/kg
subcutaneously). For dyskinesia studies animals were not trained on
apomorphine; instead they were either primed with L-DOPA (example 9) or
used `drug-naive` (example 8). Experiments consist of determining a
minimum effective dose (MED) to induce rotation for the compound in
question. Once a MED has been determined, a second experiment is
performed to determine the MED of the compound to overcome Nemonapride
block (MEDNemonapride). Nemonapride is a D2 antagonist that blocks
the D2 receptors, therefore any observed rotations would be dependent
upon activity at the D1 receptors. Finally, once the MEDNemonapride
is known a third experiment is run using the MEDNemonapride dose and
observing the effect of the D1 antagonist, SCH 23390 alone, the D2
antagonist, Nemonapride alone and finally, the effect of combined
treatment with SCH 23390 and Nemonapride. This third experiment confirms
the activity of the compound at both receptors as either antagonist alone
can only partially inhibit the rotation response induced by the test
compound while the combination treatment completely blocks all rotations
in the rats [Arnt and Hyttel, Psychopharmacology, 1985, 85 (3), 346; and
Sonsalla et al., J. Pharmacol Exp. Ther., 1988, 247 (1), 180]. This model
was validated using Apomorphine as the proof-of-principle compound for
mixed D1/D2 agonists. Compound 10 (administered subcutaneously) had a
mixed D1/D2 ratio of about 2 in this model as compared to apomorphine
that had a ratio of about 3. A D1 component could not be observed for
D2-agonists as exemplified by pramipexole and rotigotine. The data are
summarized in Table 1.

[0236] Compound 10 has the in vivo profile of a long-lasting dual D1/D2
agonist with a fast onset of action (when dosed buccally or s.c.). Thus,
it would be expected that compound 10 could be useful in treating ON/OFF
fluctuations in Parkinson's Disease. It may also be used as a `rescue
drug` for the OFF periods (freezing).

Example 8

Pharmacological Testing In Vivo II

[0237] Dyskinesia Model with Naive 6-OHDA Rats

[0238] Twenty rats with unilateral 6-OHDA lesions [see example 7 for
experimental details] were used to test induction of dyskinesia by
compound 10 (administered subcutaneously; n=7; group 1) compared to
L-DOPA/benserazide (6 mg/kg/15 mg/kg subcutaneously; n=7; group 2) and
apomorphine (1 mg/kg subcutaneously; n=6; group 3). Benserazide is a DOPA
decarboxylase inhibitor which is unable to cross the blood-brain barrier;
it is used to prevent metabolism of L-DOPA to dopamine outside the brain.

[0239] During the actual dyskinesia experiments, rats received once daily
injections of the test compounds subcutaneously and were observed for 3 h
following injection. Each animal was observed for 1 minute every 20 min
throughout the 3 h period for the presence of dyskinesias using the
Abnormal Involuntary Movement Scale (AIMS) as described previously
(Lundblad et al., Eur. J Neurosci., 15, 120 (2002)). Rats received drug
for 14 consecutive days and were scored on days 1, 2, 3, 4, 5, 8, 10 and
12. Two-way repeated measures ANOVA revealed that there was a significant
treatment effect, time effect and treatment by time interaction
(p<0.001, in all cases). Post hoc comparisons using Holm-Sidak method
indicates that animals treated with compound 10 had significantly less
dyskinesia (scores of about 30) compared to animals treated with either
L-DOPA or apomorphine (scores of about 65). There were no differences
between L-DOPA and apomorphine treated groups. Following this experiment
all rats were given subcutaneous injections of compound 10 from day 15-19
in order to determine how compound 10 influenced the severity of
dyskinesia seen in the apomorphine and L-DOPA groups. Dyskinesia scoring
was performed on day 19 of the experiment (corresponding to 5 days on
compound 10). The data showed a partial reversal of the dyskinesias
induced by L-DOPA and apomorphine to about the level of dyskinesias
induced by compound 10 (which did not cause an increase in dyskinesia in
group 1 as compared to the score of about 30 observed after 12 days of
treatment). The data are presented in Table 2.

[0240] A separate dyskinesia study addressed the reversal of L-DOPA
induced dyskinesias with either pramipexole or Compound 10. Briefly, 18
animals were treated with L-DOPA/Benserazide (6/15 mg/kg subcutaneously)
for 7 days. Animals were observed on Days 1, 3 and 5 and AIMS were
scored. The day 5 scores were then used to separate the animals into
three groups of 6 animals each. Group 1 continued with daily L-DOPA
treatment. Group 2 was treated with compound 10 (administered
subcutaneously). Group 3 was treated with pramipexole (0.16 mg/kg
subcutaneously). Treatment continued daily for 10 days and the amount of
dyskinesia was scored on days 1, 5, 9 and 10. Two-way repeated measures
analysis of variance indicated that animals treated with compound 10 had
significantly fewer dyskinesias than both the pramipexole group and the
L-DOPA/Benserazide group. The pramipexole group had significantly less
dyskinesias than the L-DOPA/Benserazide group. Hence, compound 10 had a
superior profile over pramipexole in terms of reversing dyskinesias
induced by L-DOPA. The data are presented in Table 3.

[0241] Accordingly, it is expected that dyskinesias in moderate to severe
PD based on L-DOPA-like efficacy and reversal of dyskinesias can be
treated by administration of compound 10.

Example 10

Pharmacological Testing In Vivo IV

Superiority Model

[0242] Apomorphine and L-DOPA are able to reverse motility deficits in a
mouse model of severe dopamine depletion. Both Apomorphine and L-DOPA
stimulate D1 and D2 dopamine receptors. Pramipexole, an agonist at D2
receptors is ineffective in this model. Compound 10 has been tested in
this model and exhibits a profile similar to Apomorphine and L-DOPA in
that they are able to restore locomotion in the mice. In this way,
compound 10 is `superior` to other compounds, such as Pramipexole that
target D2 receptors only. Bromocriptine is another example of a D2
agonist that does not reverse the deficits in this animal model.

[0243] The experiments were performed as follows: Mice previously treated
with MPTP (2×15 mg/kg subcutaneously) and that had stable lesions
were used and vehicle treated mice served as normal controls. MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that
causes permanent symptoms of Parkinson's disease by killing certain
neurons in the substantia nigra of the brain. It is used to study the
disease in monkeys and mice. On the day of the experiment, mice were
treated with AMPT (250 mg/kg subcutaneously) and then returned to their
home cages for 1.5 hours after which they were placed in individual cages
in the motility unit. AMPT (alpha-methyl-p-tyrosine) is a drug that
temporarily reduces brain catecholamine activity (in this case especially
dopamine levels). Three hours after the AMPT injection, rescue of
locomotive deficits was attempted with compound 10 and activity was
recorded for an additional 1.5 hours. The first 30 min of data collected
after the rescue treatment was `contaminated` due to stressing the
animals with handling and injection as evidenced by increased levels in
the vehicle controls therefore the data were analyzed using the last 1
hour of recorded data. Various compounds (all dosed subcutaneously) were
tested for their ability to reverse the motility deficits produced in
this model. L-DOPA/Benserazide, apomorphine, and compound 10 restored
locomotion in the mice in a dose-dependent manner. In contrast, the D2
agonists, pramipexole and bromocriptine did not. The data are presented
in Tables 4a-4-e.

[0244] This model was used to evaluate whether or not Compound 10 exhibits
the same superiority as L-DOPA and apomorphine over D2 agonists. A dose
response experiment for compound 10 was performed and there was a
dose-dependent reversal of the hypomotility deficits induced by severe
depletion of endogenous dopamine. A final experiment directly comparing
the effects of apomorphine, pramipexole and compound 10 in this model was
performed and confirmed that compound 10 was able to restore locomotion
in MPTP mice treated and was superior to Pramipexole in this model. The
data is presented in Table 4e.

[0245] Based on the above data in Tables 4a-4-e, and in one embodiment of
the invention, it is expected that compound 10 can be used to treat a
`moderate-to-severe PD` or `severe PD` patient population.

[0246] The lower induction of dyskinesias by compound 10 relative to
apomorphine and L-DOPA combined with the D1/D2 dissection study (and the
MPTP/AMPT mouse+MPTP marmosets studies) supports first-line treatment
with compound 10. Today, D2 agonists such as pramipexole are preferred
first-line medication due to their better `fluctuation side-effects`
profile (e.g. dyskinesias) as compared to L-DOPA. Our data demonstrates
that compound 10 is as efficacious as L-DOPA (and apomorphine) but that
it also has a better dyskinesia profile than L-DOPA and apomorphine.
Since L-DOPA is consistently more efficacious than D2 agonists like
pramipexole in all stages of PD, it is believed that compound 10 would be
an optimal drug for first-line treatment based on the combined dual D1/D2
profile in vivo, efficacy on par with L-DOPA and better than D2 agonist,
and with a dyskinesia profile better than L-DOPA.

Example 11

Pharmacological Testing In Vivo V

Anti-Parkinsonian Effects in MPTP-Treated Common Marmosets

[0247] The experiments were conducted using 6 MPTP treated marmosets (2.0
mg/kg daily for up to 5 consecutive days dissolved in sterile 0.9% saline
solution). All the animals had previously been treated with L-DOPA (12.5
mg/kg p.o., plus carbidopa 12.5 mg/kg p.o.) administered daily for up to
30 days in order to induce dyskinesia. Prior to the study all subjects
exhibited stable motor deficits including a marked reduction of basal
locomotor activity, poor coordination of movement, abnormal and/or rigid
posture, reduced alertness and head checking movements. Domperidone was
administered 60 min before any of the test compounds. Domperidone is an
antidopaminergic drug that suppresses nausea and vomiting. Locomotor
activity was assessed using test cages that are comprised of 8
photo-electric switches comprised of 8 infra-red beams which are
strategically placed in the cage and interruption of a beam is recorded
as one count. The total number of beam counts per time segment is then
plotted as time course or displayed as area under the curve (AUC) for
total activity. The assessment of motor disability was performed by a
trained observer blinded to the treatment.

[0248] L-DOPA (12.5 mg/kg, p.o.) increased locomotor activity and reversed
motor disability as previously described (Smith et al., Mov. Disord.
2002, 17 (5), 887). The dose chosen for this challenge is at the top of
the dose response curve for this drug. Compound 10 (administered
subcutaneously (0.001 or 0.01 mg/kg SC) produced a dose-related increase
in locomotor activity and reversal of motor disability tending to produce
in a response greater than for L-DOPA (12.5 mg/kg, p.o.). Compound 10
produced prolonged reversal of motor disability compared to L-DOPA and
was as efficacious as L-DOPA. This data is presented in Table 5.

Reversal of Reserpine-Induced Hypomotility by Buccal Delivery of Compound
10

[0249] Rats weighing ca. 200 g were treated with reserpine (5 mg/kg
subcutaneously as a solution in 20% aqueous solutol for which pH was
adjusted to 4 with methanesulfonic acid). Administering reserpine to rats
depletes presynaptic nerve endings from dopamine and therefore
reserpinesed rats are temporarily `parkinsonian` and unable to move
unless treated with a dopamine agonist or L-DOPA. A separate group of
four animals was treated subcutaneously with the vehicle used for
reserpine (group 1). After 23-24 hours the 24 reserpine animals were
divided into groups 2-6 with four animals in each. These were treated as
summarized below, before they were placed in activity boxes equipped with
photosensors and their locomotor activity was recorded over 3 hours.
Group 1: treated with 20% ethanol in 0.7% aqueous sodium chloride
subcutaneously. Group 2: treated with apomorphine (1 mg/kg administered
subcutaneously as an aqueous solution with pH=4. 0.02% ascorbic acid had
been added to prevent decomposition of apomorphine). Group 3: treated
with compound 10 (administered subcutaneously as solution in 20% ethanol
in 0.7% aqueous sodium chloride). Groups 4-6: treated with increasing
doses of compound 10 (administrated buccally in the upper right gingival
as a solution in 20% ethanol in 0.7% aqueous sodium chloride). The data
showed that apomorphine (1 mg/kg subcutaneously; positive control) and
compound 10 (administered subcutaneously) reversed the reserpine-induced
hypomotility. Compound 10 (administered buccally) reversed the
hypomotility. The data is summarized in Table 6.

Induction of Rotation Response in 6-OHDA Rats by Buccal Delivery of
Compound 10

[0250] We have used rats with unilateral 6-OHDA lesions to assess compound
10 for its ability to induce rotation after buccal administration [for
details on the model, see the description under example 7]. A group of
eight animals was treated with apomorphine (positive control; 0.1 mg/kg
administered subcutaneously as an aqueous solution with pH=4. 0.02%
ascorbic acid had been added to prevent decomposition of apomorphine).
Another two groups of eight animals were treated with two different doses
of compound 10 (administered buccally in the upper right gingiva as a
solution in 20% ethanol in 0.7% aqueous sodium chloride). Apomorphine
induced rotations after subcutaneous administration. Buccal delivery of
compound 10 also induced circling behavior. The data is summarized in
Table 7.

[0251] The objective of this study was to determine the plasma
concentrations of compound 10 in minipig following dosing with compound
10 (by either intravenous administration at 0.0025 mg/kg or by buccal
administration at 0.010 mg/kg and 0.040 mg/kg).

Study Design

Test and Control Articles

[0252] The test article was compound 10. The vehicles for the test article
were Sterile saline (0.9% NaCl) (intravenous administration) supplied by
Baxter, Norfolk or Ascorbic acid reconstituted in Water for Injection
(buccal administration) supplied by VWR International, Leicestershire.
Formulations were prepared on the day of dosing.

Test System and Dose Levels

[0253] Three male minipigs of the Gottingen ApS strain were supplied by
Ellegaard Gottingen, Dalmose, Denmark. At initiation of dosing, animals
were approximately 15 to 17 weeks old. Each animal was dosed once on
three separate occasions according to the following study design:

[0254] Animals were deprived of food overnight and anaesthetised with
isoflurane in oxygen (administered by facemask), prior to each dosing
occasion.

Day 1--Intravenous Administration

[0255] Intravenous administrations were performed by slow manual injection
via a temporary catheter placed in the ear vein whilst under anaesthesia,
animals were allowed to recover from the anaesthesia immediately after
dosing. Whilst anaesthetised, a catheter was inserted into the jugular
vein and secured in place for the purpose of blood collection. The
catheter was filled with heparin (250 iu/mL in 0.9% sodium chloride). The
exterior portion of the catheter was routed from the ventral neck to the
dorsum of the minipig and protected by bandaging. The distal end of the
catheter was capped and placed in a re-sealable pouch within the bandage.
The jugular catheter was retained in place and flushed with heparinised
saline every 24 hours.

Days 3 and 5--Buccal Administrations

[0256] Buccal administrations were performed by applying the test
formulation to the buccal membrane for 5 minutes while the animal was
anaesthetised. Any residual formulation remaining in the mouth after the
5 minute application was left in the mouth. Animals were allowed to
recover from the anaesthesia immediately after dosing.

Plasma Concentrations

[0257] Blood samples were taken from all animals on Day 1 following
intravenous (bolus) administration, all animals on Day 3 following buccal
administration of a low dose and all animals on Day 5 following buccal
administration of a high dose for pharmacokinetic analysis. The samples
(1.0 mL) were collected from the jugular vein (via catheter) into tubes
containing EDTA anticoagulant. Prior to addition of the blood sample, 100
microL of a stabiliser (2% beta-mercaptoethanol containing 20 mg/mL
ascorbic acid) was added to each pot. The stabiliser was prepared fresh
on each day of sample collection. Samples were collected as follows:
[0258] Day 1: 5, 10, 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12 and 16
hours post-dose [0259] Day 3: pre-dose and at 5, 10, 15, 30 and 45
minutes and 1, 2, 4, 6, 8, 12, 16 and 24 hours post-dose [0260] Day 5:
pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16
and 24 hours post-dose

[0261] The times of the blood sampling were generally adhered to. The
greatest deviation from the scheduled timepoints was one minute late at
the 5 minute timepoint on Day 3. The blood samples were centrifuged
within one hour of sample collection and the resultant plasma was frozen
prior to analysis.

[0263] The plasma concentrations of compound 10 were determined after
solid phase extraction of the plasma samples followed by high performance
liquid chromatography with tandem mass spectrometric detection (LC-MS/MS)
using a sample volume of about 100 microL.

[0264] Internal standard solution, containing the internal standard of
compound 10 was added to thawed plasma samples (100 microL aliquot). The
SPE plate (Oasis HLB, 10 mg) was conditioned with methanol (500 microL)
followed by water (500 microL). The sample (approx. 500 microL aliquot)
was transferred to the pre-conditioned SPE plate. The sample was then
passed through the cartridge, which was then washed with water:methanol
(90:10 v/v, 0.5 mL). The sample was then eluted into a fresh 96 well
polypropylene collection plate with 20 mM ammonium formate (aq):
acetonitrile: formic acid (50:50:2 v/v/v, 250 microL). The organic
component of the eluted samples was then evaporated under a gentle stream
of nitrogen until approximately 50% of the original volume was remaining.
An aliquot (100 microL) of a solution containing 20 mM ammonium formate
(aq) and 0.5% formic acid:acetonitrile (90:10 v/v) together with 4 mg/mL
ascorbic acid was added to the remaining aqueous component of the sample
in each well, vortex mixed, centrifuged (3500 rpm, 10 minutes, room
temperature) prior to being submitted for UHPLC-MS/MS analysis.

[0265] Concentrations of compound 10 in calibration standards, QC samples
and study samples were determined using least squares linear regression
with 1/x weighting for compound 10. The plasma concentrations of compound
10 were determined after solid phase extraction of the plasma samples
followed by high performance liquid chromatography with tandem mass
spectrometric detection (LC-MS/MS). The method was validated and has a
lower limit of quantification (LLOQ) of 10 pg/mL using 100 microL of
plasma.

[0271] A representative chromatogram generated using the above procedure
and acquired during the determination of compound 10 in minipig plasma is
presented in FIG. 3. As the quantification of compound 10 was based upon
peak height ratios, the integrations on some of the chromatograms include
additional noise and interference peaks to ensure the correct peak height
is measured.

[0273] Following single intravenous bolus administration of compound 10 at
0.0025 mg/kg to male minipigs, maximum plasma concentrations of compound
10 were observed at 5 minutes post-dose, i.e. at the first blood sampling
time post intravenous administration. Plasma concentrations of compound
10 appeared to decline in a generally bi-phasic manner with an apparent
terminal elimination half-life (t1/2) ranging from 3.4 to 4.3 hours, with
the start of the apparent terminal phase occurring at 4 hours post-dose.

[0274] Over the 16 hour sampling period, plasma concentrations were
quantifiable (i.e. above the LLOQ of 10 pg/mL) up to 12 hours post-dose
in 2 animals, with concentrations estimated at 16 hour post-dose as
levels were above 20% of the LLOQ. In one animal (animal 3), plasma
concentrations were greater than the LLOQ throughout the 16 hour period.

Plasma Concentrations of Compound 10 Following Buccal Administration

[0275] Plasma concentrations of compound 10 in minipigs following buccal
administration (0.010 mg/kg). The data are summarized in Table 9.

[0277] Following single buccal administration of compound 10 at 0.010
mg/kg and 0.040 mg/kg to the male minipig, compound 10 was rapidly
absorbed, with compound 10 being quantifiable in plasma at 5 minute
post-dose. Maximum plasma concentrations were observed at about 0.75
hours post-dose, with the exception of animal 1 at the 0.040 mg/kg dose
level with a delayed tmax of 1 hour post-dose. After attainment of Cmax,
plasma concentrations of compound 10 appeared to decline in a bi-phasic
manner, with mean apparent terminal half-lives of 5.1 and 5.6 hours at
the 0.010 mg/kg and 0.040 mg/kg dose levels, respectively.

[0278] Over the 24 hour sampling period, plasma levels of compound 10
remained above the LLOQ, apart from 2 animals following the 0.010 mg/kg
dose where plasma concentrations were either estimated (as levels were
above 20% of the LLOQ; 16 hour post-dose for 1M; 24 hour post-dose for
2M), or were not quantifiable (being <20% of LLOQ; 24 h post-dose for
1M).

[0280] Systemic exposure to compound 10 increased in a supra-proportional
manner over the 0.010 mg/kg and 0.040 mg/kg dose range with
AUC0-∞ and Cmax increasing by 12-fold over the 4-fold
increase in dose. The bioavailability of compound 10 following buccal
administration was dose dependent, ranging from 30 to 42% at 0.010 mg/kg,
increasing to 73 to 136% at 0.040 mg/kg The dose normalised AUC0-∞
and Cmax for compound 10 are presented graphically in FIGS. 3 and 4,
respectively.

[0282] Absorption of compound 10 was rapid following single buccal
administration of compound 10, with maximum plasma concentrations being
observed at 0.75 to 1 hours post-dose. Plasma concentrations of compound
10 appeared to decline in a bi-phasic manner and the apparent terminal
elimination half-life was independent of dose, with values ranging from
3.1 to 5.6 hours in individual animals.

[0283] Following buccal administration, systemic exposure to compound 10
appeared to increase in a supra-proportional manner with a 12-fold
increase in both AUC0-∞ and Cmax over the 0.010 to 0.040 mg/kg dose
range. Due to the non-linearity in exposure, bioavailability of compound
10 was dose dependent with mean values of 31 to 35% at 0.010 mg/kg
increasing to 105 to 122% at 0.040 mg/kg.

Example 15

Pharmacological Testing In Vivo IX

Induction of Circling Behaviour in a Rat Model of Parkinson's Disease by
Intranasal Administration of Compound 10

[0284] Animals were generated as described under example 7. Four groups of
animals were dosed with various doses of compound 10 (group 1, 1
microg/kg; group 2, 10 microg/kg; group 3, 25 microg/kg; group 4, 50
microg/kg). In all cases, compound 10 was administered in one of the
nostrils in a volume of 20 microL of a solution of the appropriate
concentration in 20% ethanol in 0.7% aqueous sodium chloride containing
0.02% ascorbic acid. The drug solution was applied to one of the nostrils
and the nose was gently massaged to ensure distribution of the
administered solution over the nasal mucosa. The degree of rotation
behaviour of the animals was recorded over the next 3 hours. The data are
presented in Table 11.

Induction of Rotation Response in 6-OHDA Rats by Transdermal Delivery of
Compound 10

[0285] We have used rats with unilateral 6-OHDA lesions to assess compound
10 for its ability to induce rotation after transdermal administration
[for details on the model, see the description under example 7]. Three
groups of six animals were treated with different doses of compound 10
administered transdermally. Compound 10 (24 mg) was suspended in a
mixture of 0.02% ascorbic acid and 20% ethanol in saline (9 mL); the
resulting suspension was diluted with dimethyl sulfoxide (0.45 mL). The
appropriate amount of this formulation was applied to the ears of the
animals. The ears were rubbed gently before the rotation response of the
animals was assessed over 3 h. Transdermal delivery of compound 10
induced circling behavior in all three groups. The data is summarized are
Table 12.